Pharmaceutical Regulatory Affairs: Open Access

Dendritic cell (DC)-based immunotherapy has been developed against various types of cancers. To develop and promote regenerative medicine and cell therapy in Japan, the Act on the Safety of Regenerative Medicine and the Revised Pharmaceutical Affairs Law have been enforced since November 25, 2014. Therapeutic vaccination with active DCs was evaluated under the legal framework. Cancer vaccination therapies with autologous monocyte-derived mature DCs are principally attributed to the presence of tumor-associated antigens. Clinical studies and trials should be conducted in accordance with legislation for approval of either DC-based cancer therapy or DC vaccine products. The following issues with regards to DC-based vaccination and vaccine products for clinical use may be raised: 1) Manufacturing of DCs according to the standard grade of Good Gene, Cellular, and Tissue-based Products (GCTP) Manufacturing Practice; 2) Peptides that target cancer-associated antigens for any cancer patient; 3) Quality of immunological analyses as proof of concept; and 4) Optimization of DC vaccines as add-ons to chemotherapeutic drugs and/or radiotherapy to predict potential biomarkers of response. Phase II clinical trials that are covered by Advanced Medical Care System would be conducted on DC vaccine pulsed with Wilms’ tumor 1-specific MHC class I/II-restricted epitopes for pancreatic cancer. The designed clinical trial adopted with new technology could reveal the efficacy of DC vaccine in combination with optimized therapies. This would be relevant to the development of personalized therapy in cancer patients.

Legal framework for pharmaceutical legislation in the European Union is complex but clear in its principles, with the main objective of safeguarding public health. The regulation of (traditional) herbal medicinal products is covered by regulations, directives and scientific guidelines to ensure safety and efficacy. Pharmaceutical quality criteria for herbal medicinal products is defined in the amended Directive 2001/83/EC and Directive 2003/63/EC and complemented with several scientific guidelines which ensure that all herbal medicinal products in the European market are manufactured or imported only by authorized manufacturers which have also followed the Good Manufacturing Practices adopted by the Community. This will lead to high quality herbal substances, herbal preparations and herbal medicinal products which can be placed in the market through different types of application: full application, well-established use or traditional use marketing authorization, according to the efficacy data. This article provides an updated review on the specific characteristics of these groups of medicinal products before they are granted a marketing authorization.

The future of research in the treatment of hernia is directed mainly in two ways. The first is in genetic research, focusing on the goal of preventing the occurrence of hernia. The second (and more realistic), addresses the introduction of a new generation of biomaterials and surgical techniques that minimize aggression hernia repair, reduce surgical time and facilitate post-operative recovery of these patients. In this second line of action appear the most important advances in the field of minimally invasive techniques and materials used to repair the hernia pathology.

The development of materials currently employed in hernia surgery has focused almost entirely on improvements on the screens, coatings and methods of fixation. The point has been reached of trying to unite these concepts, creating new self-adhesive mesh, coated meshes of various substances that incorporate improvements in both fields of research.

The pharmaceutical industry is emerging as a significant industrial sector with tremendous potential for providing innovative drugs to treat life-threatening diseases as well as for providing economical generic alternatives of supreme quality. Hence this sector is not only responsible to provide the much desired boost to the health of the society, especially of the developing countries, but also it is a competitive yet profitable sector from a business perspective. Currently, the primary focus of the pharmaceutical industry is to raise the bar for the quality, safety and efficacy of the drug products that are made available in the global market place. Product quality, price of raw materials [API (active pharmaceutical ingredient) and excipients] and market return competition are vital factors that determine the longevity or existence and profitability of a company in the crowded pharmaceutical market. . Hence these critical factors receive special consideration from drug product manufacturers. Active Pharmaceutical Ingredient (API) is the primary constituent of a pharmaceutical drug product that governs the final cost of the drug product as well as the commercial profit earned by the company. Most of the major generic drug manufacturing companies have their own API manufacturing facility and hence may not prefer to screen independent API suppliers as part of their generic drug development plan to procure additional API. Contradictorily, the generic drug manufacturers who do not synthesize the API themselves are dependent on external and independent API manufacturers for procurement of the API. Such generic drug manufacturing companies have to select suitable API suppliers by adapting a risk aversive approach. This article presents an informed and comprehensive discussion on the primary and alternate API supplier selection processes for generic drug products manufacturing firms. This API supplier selection process can be categorized into several stages which include preliminary assessment, documents review, samples analysis, onsite or offsite audit, results evaluation and final approval or rejection. This API selection process includes the anticipated product specific risk assessment with relation to API characteristics, specifications, analytical results, document review observations and inspection results. A generic drug product manufacturing company can choose an alternative API supplier or change the existing API supplier either during the development phase or after development of the drug product. Generic drug product manufacturing companies should rework on development activities if any API supplier change happens during the development phase. API supplier change or addition of an alternative API supplier has to be followed as per SUPAC guidance for US market and VARIATION filing procedures for European market.

There are so many ISO documents to understand and utilize for validation studies and routine control. A biological indicator (BI) is essential for conducting sterilization validation and routine control. ISO 11138-1 and ISO 14161 are the major documents to follow for BI manufacturers and BI users, respectively. In ISO 11138-1, BI manufacturers must utilize a BI with 10⁶ CFU/carrier as an initial population for validation studies. For routine control, it is approved to use an initial BI population of 10⁵ CFU/carrier according to ISO 11138-1. In ISO 14161 BI users need not imitate BI manufacturers and less than 10⁶ CFU/carrier BI is approved for use in validation studies and routine control. According to ISO 14161 for BI users, the initial population must be identical for validation studies and routine control. For the BI user, there are four types of procedures for sterilization validation and routine control. These are the half-cycle, over-kill, combined BI/bioburden and the absolute bioburden methods. A BI with An initial population of 10⁶ CFU/ carrier must be used for validation studies by BI manufacturers according to ISO 11138-1, but BI users can elect to use a commercially available BI with more than 103 CFU/carrier as the BI for validation studies and routine control as described in ISO 14161. The approved SAL was defined to be 10^-6 and this is unchanged for both BI users and BI manufacturers. Therefore, from the initial population of 10⁶ CFU (colony forming unit)/carrier to a SAL of 10^-6, the survivor curve must be straight and tailing is not allowed as described below (ISO 11138-1). The BI used for gas plasma sterilization, spores of Geobacillus stearothermophilus ATCC 7953, has characteristics that do not result in a tailing phenomenon. A linear survival curve is obtained from an initial population of 10⁶ CFU/carrier to a SAL 10^-6 for all sterilization procedures tested, demonstrating that inactivation kinetics are first order and allowing calculation of the D (decimal reduction) value from the dose or time to decrease 1 log. Chemical indicators (CI) are not approved for use in validation studies; only the use of BI is approved. CIs are only approved for use as a supporting method during routine control according to ISO 11140-1 and 14161. Only a BI is approved for both validation studies and routine control according to ISO 14161.

Even when using vegetative cells, a tailing phenomenon can be observed in survivor curves in engineering researcher’s papers on gas plasma sterilization. This indicates that even disinfection was not even achieved. By definition, sterilization is a process that kills all types of microorganisms including bacterial spores and vegetative cells. In contrast, disinfection kills only vegetative cells and does not kill bacterial spores. Tailing of a survivor curve is often caused by clumping of the biological indicator (BI), and engineering researchers who make their own BI without critical knowledge, appropriate techniques and confidential know-how to avoid such clumping frequently publish nonlinear survivor curves. Preparation of a monolayer of BI is quite a difficult task even for BI manufacturers and it requires proprietary information. Therefore, engineering researchers should purchase commercially available BI. Among the BIs on the market, I recommend purchasing BI from Merck Co., as clumping was found to be minimal based on results of scanning electron microscopy (SEM) observation. When such a tailing phenomenon is observed, a SAL of 10^-6 cannot be attained, and therefore no D value (decimal reduction value) can be determined and the exposure time for a 9 or 12 log reduction remains undefined. The D value must be determined from the straight line of a 9 log or 12 log reduction survivor curve, and there can only be one D value per microorganism; there is never more than one D value per one microorganism. The BI is defined as the most tolerant microorganism (typically bacterial spores) to the sterilization procedure being used, so if the BI is killed, then other contaminants (microorganisms) can be speculated to also be killed. Therefore, the use of a BI is essential in sterilization validation studies and routine control. Strategies to avoid clumping, tailing phenomena and to attain a SAL of 10^-6 will be considered in this article.