FDA and NIST collaboration on standards development activities supporting innovation and translation of regenerative medicine products

The development of standards for the field of regenerative medicine has been noted as a high priority by several road-mapping activities. Additionally, the U.S. Congress recognizes the importance of standards in the 21st Century Cure Act. Standards will help to accelerate and streamline cell and gene therapy product development, ensure the quality and consistency of processes and products, and facilitate their regulatory approval. Although there is general agreement for the need of additional standards for regenerative medicine products, a shared understanding of standards is required for real progress toward the development of standards to advance regenerative medicine. Here, we describe the roles of standards in regenerative medicine as well as the process for standards development and the interactions of different entities in the standards development process. Highlighted are recent coordinated efforts between the U.S. Food and Drug Administration and the National Institute of Standards and Technology to facilitate standards development and foster science that underpins standards development.     

Metabolomics Standards Workshop and the development of international standards for reporting metabolomics experimental results

Informatics standards and controlled vocabularies are essentialfor allowing information technology to help exchange, manage,interpret and compare large data collections. In a rapidly evolvingfield, the challenge is to work out how best to describe, butnot prescribe, the use of these technologies and methods. AMetabolomics Standards Workshop was held by the US NationalInstitutes of Health (NIH) to bring together multiple ongoingstandards efforts in metabolomics with the NIH research community.The goals were to discuss metabolomics workflows (methods, technologiesand data treatments) and the needs, challenges and potentialapproaches to developing a Metabolomics Standards Initiativethat will help facilitate this rapidly growing field which hasbeen a focus of the NIH roadmap effort. This report highlightsspecific aspects of what was presented and discussed at the1st and 2nd August 2005 Metabolomics Standards Workshop.      

Standards requirements for systems biology approaches to health care: mitochondrial proteomics

A review of the standards needs of the mitochondrial proteomics communities is presented based on the presentations and discussions at National Institute of Standards and Technology (NIST) workshop, Systems Biology Approaches to Health Care: Mitochondrial Proteomics, held on September 17-18, 2002. The mitochondrial proteomics areas addressed for standards needs are model systems, methods and data. This review outlines the challenges in the field, proposes standards efforts that the community would like to see pursued to meet those challenges, and is followed by a summary and NIST's planned efforts to address these standards requirements.     

The Functional Genomics Experiment model (FuGE): an extensible framework for standards in functional genomics

The Functional Genomics Experiment data model (FuGE) has been developed to facilitate convergence of data standards for high-throughput, comprehensive analyses in biology. FuGE models the components of an experimental activity that are common across different technologies, including protocols, samples and data. FuGE provides a foundation for describing entire laboratory workflows and for the development of new data formats. The Microarray Gene Expression Data society and the Proteomics Standards Initiative have committed to using FuGE as the basis for defining their respective standards, and other standards groups, including the Metabolomics Standards Initiative, are evaluating FuGE in their development efforts. Adoption of FuGE by multiple standards bodies will enable uniform reporting of common parts of functional genomics workflows, simplify data-integration efforts and ease the burden on researchers seeking to fulfill multiple minimum reporting requirements. Such advances are important for transparent data management and mining in functional genomics and systems biology.     

Extending Standards for Genomics and Metagenomics Data: A Research Coordination Network for the Genomic Standards Consortium (RCN4GSC)

Through a newly established Research Coordination Network for the Genomic Standards Consortium (RCN4GSC), the GSC will continue its leadership in establishing and integrating genomic standards through community-based efforts. These efforts, undertaken in the context of genomic and metagenomic research aim to ensure the electronic capture of all genomic data and to facilitate the achievement of a community consensus around collecting and managing relevant contextual information connected to the sequence data. The GSC operates as an open, inclusive organization, welcoming inspired biologists with a commitment to community service. Within the collaborative framework of the ongoing, international activities of the GSC, the RCN will expand the range of research domains engaged in these standardization efforts and sustain scientific networking to encourage active participation by the broader community. The RCN4GSC, funded for five years by the US National Science Foundation, will primarily support outcome-focused working meetings and the exchange of early-career scientists between GSC research groups in order to advance key standards contributions such as GCDML. Focusing on the timely delivery of the extant GSC core projects, the RCN will also extend the pioneering efforts of the GSC to engage researchers active in developing ecological, environmental and biodiversity data standards. As the initial goals of the GSC are increasingly achieved, promoting the comprehensive use of effective standards will be essential to ensure the effective use of sequence and associated data, to provide access for all biologists to all of the information, and to create interdisciplinary opportunities for discovery. The RCN will facilitate these implementation activities through participation in major scientific conferences and presentations on scientific advances enabled by community usage of genomic standards.     

Pluripotent stem cell heterogeneity and the evolving role of proteomic technologies in stem cell biology

Stem cells represent obvious choices for regenerative medicine and are invaluable for studies of human development and drug testing. The proteomic landscape of pluripotent stem cells (PSCs), in particular, is not yet clearly defined; consequently, this field of research would greatly benefit from concerted efforts designed to better characterize these cells. In this concise review, we provide an overview of stem cell potency, highlight the types and practical implications of heterogeneity in PSCs and provide a detailed analysis of the current view of the pluripotent proteome in a unique resource for this rapidly evolving field. Our goal in this review is to provide specific insights into the current status of the known proteome of both mouse and human PSCs. This has been accomplished by integrating published data into a unified PSC proteome to facilitate the identification of proteins, which may be informative for the stem cell state as well as to reveal areas where our current view is limited. These analyses provide insight into the challenges faced in the proteomic analysis of PSCs and reveal one area--the cell surface subproteome--that would especially benefit from enhanced research efforts.     

Prospects for translational regenerative medicine

Translational medicine is an evolutional concept that encompasses the rapid translation of basic research for use in clinical disease diagnosis, prevention and treatment. It follows the idea "from bench to bedside and back", and hence relies on cooperation between laboratory research and clinical care. In the past decade, translational medicine has received unprecedented attention from scientists and clinicians and its fundamental principles have penetrated throughout biomedicine, offering a sign post that guides modern medical research toward a patient-centered focus. Translational regenerative medicine is still in its infancy, and significant basic research investment has not yet achieved satisfactory clinical outcomes for patients. In particular, there are many challenges associated with the use of cell- and tissue-based products for clinical therapies. This review summarizes the transformation and global progress in translational medicine over the past decade. The current obstacles and opportunities in translational regenerative medicine are outlined in the context of stem cell therapy and tissue engineering for the safe and effective regeneration of functional tissue. This review highlights the requirement for multi-disciplinary and inter-disciplinary cooperation to ensure the development of the best possible regenerative therapies within the shortest timeframe possible for the greatest patient benefit.     

Use of impedance methods for testing bactericidal activity of antiseptics

Standards PN-EN 1040 and EN 12054 describe test methods and minimum requirements for bactericidal activities of antiseptics. However, standard procedures are time consuming and require 48 hours of incubation. New alternative technique based on impedimetric procedure provides possibilities to reduce this time to several hours. The Bactometer (BioMerieux, Vitek System, USA) is a fully automated impedance technology system used to microbial quantitation of products. Impedance measures microbial activity by electrical methods. The aim of the study was to adaptate the impedimetric method utilising Bactometer--system to microbiological activity control of chemical antiseptics. Eight different products were utilised throughout the study. The samples for classical and alternative method were prepared in the same way as described in standards. The method of choice was dilution-neutralization method. All procedures conducted in Bactometer were verified by plate count method. The high correlation was observed between results obtained by normative methods and impedimetric measurement. All tested products meet requirements. The procedure utilising the Bactometer, provides a rapid and accurate system for the determination of bacterial content. The results of validation carried out during this study indicate, possibility to use impedimetric method alternatively to traditional methods.     

Standard reporting requirements for biological samples in metabolomics experiments: microbial and in vitro biology experiments

With the increasing use of metabolomics as a means to study a large number of different biological research questions, there is a need for a minimal set of reporting standards that allow the scientific community to evaluate, understand, repeat, compare and re-investigate metabolomics studies. Here we propose, a first draft of minimal requirements to effectively describe the biological context of metabolomics studies that involve microbial or in vitro biological subjects. This recommendation has been produced by the microbiology and in vitro biology working subgroup of the Metabolomics Standards Initiative in collaboration with the yeast systems biology network as part of a wider standardization initiative led by the Metabolomics Society. Microbial and in vitro biology metabolomics is defined by this sub-working group as studies with any cell or organism that require a defined external medium to facilitate growth and propagation. Both a minimal set and a best practice set of reporting standards for metabolomics experiments have been defined. The minimal set of reporting standards for microbial or in vitro biology metabolomics experiments includes those factors that are specific for metabolomics experiments and that critically determine the outcome of the experiments. The best practice set of reporting standards contains both the factors that are specific for metabolomics experiments and general aspects that critically determine the outcome of any microbial or in vitro biological experiment.     

Data standards: a call to action

Access to data is something that every molecular biologist takes for granted nowadays, but data alone is of little use unless it is made available in a useable form through the development and global uptake of data standards. The challenge of standards development has been taken up by grass-roots movements working within several different branches of the biomedical research community. Many of these initiatives are proving extremely successful; for example, the Gene Ontology, which provides a controlled vocabulary for describing the properties of gene products, the Microarray Gene Expression Data Society's standards for describing microarray experiments, and the emerging standards developed by the Proteomics Standards Initiative are gaining broad acceptance. Standards development now faces its greatest ever challenge--the integration of diverse data types to fulfill the goals of systems biology. Now is the time for the communities that are developing these standards, the funding bodies that have invested so heavily in high-throughput data generation, and the publishers of biomedical research papers to cooperate fully to make the goals of integrated data analysis a reality.     

Transitioning from development to commercial: risk-based guidance for critical materials management in cell therapies

A key hurdle to ensuring patient access to cell and gene therapies (CGTs) and continued growth of the industry is the management of raw materials. The combination of rapid growth, individual product and process complexity and limited industry-specific guidance or awareness presents non-obvious risk mitigation challenges for transitioning from development to clinical application. Understanding, assessing and mitigating the varied raw material risks for CGT products during product and clinical development are critical for ensuring smooth transitions into commercialization and for preventing interruption of product supply to patients. This article presents a risk-based approach driven by concerns for patient safety that can help focus and coordinate efforts to address the most critical risk factors. Highlighted are some of the highest risk materials common to the manufacture of many CGTs, including the primary starting material, culture media, reagents and single-use components. Using a hypothetical gene-edited cell therapy as an example, we describe the general manufacturing process and subsequently incorporate the described methodology to perform a sample risk assessment. The practical approach described herein is intended to assist CGT manufacturers and suppliers in actively assessing materials early in development to provide a basic starting point for mitigating risks experienced when translating CGT products for clinical and long-term commercial application.     

Compliance and cost control for cryopreservation of cellular starting materials: An industry perspective

Over the last decade, cancer immunotherapy has progressed from an academically interesting field to one of the most promising forms of new treatments in which not the cancer but the immune system is treated. In particular, genetic modification for purposeful redirection of autologous T cells is providing hope to many treatment-resistant patients. This personalized form of medicine is radically different from more traditional oncologic drugs. With these evolving medical advancements and more cellular therapies becoming available, some regulatory agencies have created new regulatory requirements to manage the production of these types of products. The regulations are specifically suited for the manufacture of gene and cell therapy products, as they use a risk-based approach towards product development and manufacturing, when there is limited characterization available. The correct interpretation of how and when requirements apply is crucial, since theoretical approaches to implementing GMP can easily lead to disproportionate and unwarranted restrictions that may not address the specific risks that regulators were intending to control. This is especially relevant for cell collection and biopreservation preceding the manufacturing process for products manufactured from autologous T cells. Both the fresh and cryopreserved apheresis materials can be filed as minimally manipulated starting materials to the authorities. The preservation of such cellular material can then routinely be managed using the available regulations for tissues and cells, allowing for a more fit-for-purpose approach to the control measures implemented.     

A practical validation approach for virus titer testing of avian infectious bursal disease live vaccine according to current regulatory guidelines

The method for virus titer determination of avian infectious bursal disease (IBD) live vaccine, developed long before regulatory validation guidelines is a cell culture based biological assay intended for use in vaccine release testing.The aim of our study was to perform a validation, based on fit-for-purpose principle, of an old 50% tissue culture infectious dose (TCID₅₀) method according to Guidelines of the International Cooperation on Harmonization of Technical Requirements for Registration of Veterinary Medicinal Products (VICH).This paper addresses challenges and discusses some key aspects that should be considered when validating biological methods. A different statistical approach and non-parametric statistics was introduced in validation protocol in order to derive useful information from experimental data. This approach is applicable for a wide range of methods.In conclusion, the previous virus titration method had showed to be precise, accurate, linear, robust and in accordance with current regulatory standards, which indicates that there is no need for additional re-development or upgrades of the method for its suitability for intended use.     

Proposal for a standard representation of two-dimensional gel electrophoresis data

The global analysis of proteins is now feasible due to improvements in techniques such as two-dimensional gel electrophoresis (2-DE), mass spectrometry, yeast two-hybrid systems and the development of bioinformatics applications. The experiments form the basis of proteomics, and present significant challenges in data analysis, storage and querying. We argue that a standard format for proteome data is required to enable the storage, exchange and subsequent re-analysis of large datasets. We describe the criteria that must be met for the development of a standard for proteomics. We have developed a model to represent data from 2-DE experiments, including difference gel electrophoresis along with image analysis and statistical analysis across multiple gels. This part of proteomics analysis is not represented in current proposals for proteomics standards. We are working with the Proteomics Standards Initiative to develop a model encompassing biological sample origin, experimental protocols, a number of separation techniques and mass spectrometry. The standard format will facilitate the development of central repositories of data, enabling results to be verified or re-analysed, and the correlation of results produced by different research groups using a variety of laboratory techniques.     

Maßgeschneiderte Mikroorganismen

Tailor‐made microorganisms Microbial diversity provides unlimited resources for the development of novel industrial processes and products. Since the beginning of the 20th century microorganisms have been successfully applied for the large scale production of bio‐based products. In recent years, modern methods of strain development and Synthetic Biology have enabled biotech engineers to design even more sophisticated and tailor‐made microorganisms. These microbes serve industrial processes for the production of bulk chemicals, enzymes, polymers, biofuels as well as plant‐derived ingredients such as Artemisinin in an ecologically and economically sustainable and attractive fashion. In the future, production of advanced biofuels, microbial fuel cells, CO₂ as feedstock and microbial cellulose are research topics as well as challenges of global importance. Continuous efforts in microbiology and biotechnology research will be pivotal for white biotechnology to gain more momentum in transforming the chemical industry towards a knowledge based bio‐economy.     

后基因组时代微生物天然产物高效发掘体系设计与展望

微生物天然产物具有丰富的化学结构多样性和诱人的生物活性,持续启迪着创新医药和农药的发现。近年来,随着高通量测序技术的快速发展,巨大的微生物基因组数据揭示了多样生物合成和新颖天然产物的潜能远高于以前的认知。然而,如何高效地激活隐性的生物合成基因簇 (BGCs) 并识别相应的化合物,以及避免已知代谢产物的重复发现等挑战依然严峻。本文描述了面对这些问题时基因组学、生物信息学、机器学习、代谢组学、基因编辑和合成生物学等新技术在发现药用先导化合物过程中提供的机遇;总结并论述了在潜力菌株优选、BGCs的生物信息学预测、沉默 BGCs的高效激活以及目标产物的识别和跟踪方面的新见解;提出了基于潜力菌株选择和多组学挖掘技术从微生物天然产物中高效发现先导结构的系统线路 (SPLSD),并讨论了未来天然产物药用先导发现的机遇和挑战。     

Guideline for the collection and preparation of non-transfusion autologous platelet concentrate or platelet-rich plasma from patients in hospitals

Non-transfusion autologous platelet concentrate (PC), also known as platelet-rich plasma (PRP), has become a widely used blood-based product in the field of sports medicine, rehabilitation medicine, and clinical medicine. Currently, autologous PC or PRP operation procedures (personnel qualification, equipment, methods, environment and tracking, protocols, preparations, techniques and product quality control) lack unified specifications and standards, which lead to inconsistencies in the quality of PC or PRP products made by medical institutions, affecting treatment efficiency. In blood collection and supply organizations, the collection of blood components has a series of standard operating procedures (SOP) and quality assurance which can be referenced by medical institutions to standardize the preparation and usage of patient autologous PC or PRP products. According to Technical Standards for Preparation of Platelet Concentrate for Blood Stations, we compiled this guideline for medical staff to prepare high quality and reliable PC or PRP products in order to promote the standardization of PC or PRP in clinical application.     

A changing time: the International Society for Cellular Therapy embraces its industry members

The last decade has seen a dramatic rise in the development of new cellular therapeutics in a wide range of indications. There have been acceptable safety profiles reported in early studies using blood-derived and adherent stem cell products, but also an inconsistent efficacy record. Further expansion has been hindered in part by a lack of capital (both private and public) and delayed entry into the cell therapy space by large healthcare and pharmaceutical companies, those members of the industry most reliably able to initiate and maintain advanced-phase clinical trials. With recognition that the International Society for Cellular Therapy (ISCT) is uniquely positioned to serve the global translational regenerative medicine research community as a network hub for scientific standards and policy, the ISCT commissioned the establishment of an Industry Task Force (ITF) to address current and future roles for industry. The objectives of the ITF were to gather information and prioritize efforts for a new Commercialization Committee (CC) and to construct innovative platforms that would foster constructive and synergistic collaborations between industry and ISCT. Recommendations and conclusions of the ITF included that the new CC: (1) foster new relationships with therapeutic and stem cell societies, (2) foster educational workshops and forums to cross-educate and standardize practices, (3) create industry subcommittees to address priority initiatives, with clear benchmarks and global implementation, and (4) establish a framework for a greater industry community within ISCT, opening doors for industry to share the new vision for commercialization of cell therapy, emphasizing the regenerative medicine space.     

Cell and gene therapy manufacturing capabilities in Australia and New Zealand

Cell and gene therapy products are rapidly being integrated into mainstream medicine. Developing global capability will facilitate broad access to these novel therapeutics. An initial step toward achieving this goal is to understand cell and gene therapy manufacturing capability in each region. We conducted an academic survey in 2018 to assess cell and gene therapy manufacturing capacity in Australia and New Zealand. We examined the following: the number and types of cell therapy manufacturing facilities; the number of projects, parallel processes and clinical trials; the types of products; and the manufacturing and quality staffing levels. It was found that Australia and New Zealand provide diverse facilities for cell therapy manufacturing, infrastructure and capability. Further investment and development will enable both countries to make important decisions to meet the growing need for cell and gene therapy and regenerative medicine in the region.