Stem Cell Clinical Trials and the Challenges


Stem Cell Clinical Trials and the Challenges The therapeutic stem cell and Advanced Therapeutic Medicinal Product (ATMP) market is continuing to develop. Over the last two years the focus of industry discussion groups within the UK has moved forward from research techniques during development to the challenges of GMP manufacturing these products. Once manufacturing issues are resolved focus will move onto the challenges of stem cell clinical trials. The difficulties of obtaining approval from authorities to conduct the trials will be the main focus of the sponsor. With these challenges ahead, there may be little time to focus on the actual method of labelling, storage and distribution of the product to the trial sites. Challenges of Stem Cell Clinical Trials Phase I trials are generally conducted at a single site with a single investigator and a close relationship between the investigator and the sponsor. The investigator in these trials is often a pioneer in their field and closely involved with the development of the product. Trials involving autologous products require collection of cells, processing of the cells and delivery back to the cell donor; this whole operation may be conducted on a single site or alternatively it may require transport to a separate site for cell processing and then return of the material to the same patient. Although the manipulation of the material and the technology to process the cells is extremely complex, the logistics of the trial are relatively simple. It requires secure traceability of the sample, obtained by following good manufacturing practice (GMP) guidelines and a validated shipper, which transports the material at the desired temperature between the patient and the processing site. Following production and labelling the material will require confirmation that it is GMP compliant; in the EU this is confirmed by a Qualified Person (QP). At Phase II the study is likely to take place at more than one investigator site. For autologous treatments this has the added complication of more than one patient’s treatment being processed at the same time. Traceability of samples is critical and the synchronisation of patients, the manufacturing site and QP availability becomes more complex. Competent project management and good planning should overcome these difficulties. Additionally tracking systems for these samples using patient biometrics are being developed which would flag up an incorrect sample being returned to a patient. Allogeneic products are derived from stem cells which are used to treat people other than the donor. These cells are typically manufactured in batches, on a larger scale and may be intended for use in trials in a number of countries. Labelling Solutions One issue faced with clinical trials of ATMP products is ensuring regulatory compliant labelling. The primary containers must be labelled during the manufacture and prior to freezing. Consideration needs to be given to the labelling process of the primary containers ,once frozen to -80 or -196??C, the primary container cannot be labelled , therefore producing bulk unlabelled batches and then determining which trials the stock will be allocated to at a later date is not possible. Distribution Once the product is packed in primary containers (units), it may be shipped to a second site for secondary packaging, storage and distribution to clinical sites. This is similar to the logistics of more traditional pharmaceuticals. For example, bulk batches of labelled material could be shipped from the manufacturer to a storage site. These could then be assembled into kits in a cryostorage box, containing enough material to dose one patient. Alternatively, to avoid cell wastage material could be handled with a ‘just in time’ packing method, which has proved successful in more conventional drug trials where the drug is either very scarce or very expensive. Receipt at the investigational site would be simpler using the kit model, the site would not have to record receipt of each individual tube into inventory. In addition the secondary container could be tamper proof, giving added protection to the primary tubes. This can be particularly important if the cells are to be stored at the investigator site’s own cryostorage facilities rather than in the nitrogen shipper, as cross contamination could be a risk. None of the issues in the clinical trial supply chain of stem cell products are impossible to overcome as long as there is consideration very early in the trial process for the method of labelling, distribution and on site storage of the product. Even for conventional products, it is a challenge to persuade sponsors to carefully consider the clinical supply chain at a sufficiently early stage. For stem cell products this is perhaps even more essential and it will be a continued challenge over the coming years for the supply chain companies capable of supporting ATMPs to engage with sponsors at an early enough stage to ensure the provision of a service that can meet patient recruitment needs and is affordable for the sponsors.

Biomass Resources


Whether based on a large scale instead of conventional fossil fuels, and biomass will be divided into traditional and modern biomass. Including traditional biomass energy use in rural life: firewood, straw, rice straw, rice husk and other agricultural production and animal manure and other waste; modern large-scale application of biomass is biomass, including modern forestry production of waste, bagasse and municipal solid waste.According to different sources, would be suitable for biomass energy use into forestry resources, agricultural resources, domestic sewage and industrial organic wastewater, municipal solid waste and animal manure and other five categories.(1) Forest Resources forest biomass resources is the process of forest growth and forest production to provide biomass sources, including firewood in the forest tending and thinning operations in scattered timber, residual branches, leaves and wood chips, etc.; timber harvesting transport and processing of the branches, sawdust, wood chips, Shaotou, slab and cut top; forestry by-products of waste, if the shell and stone, etc.(2) agricultural resources agricultural biomass resource is agricultural crops (including energy crops); agricultural production process waste, such as when left in the fields harvesting crops within the crop stalks (corn stalks, sorghum stalks, wheat straw, rice straw, Doujie and cotton stalks, etc.); agricultural processing waste, such as the agricultural production process in the remaining rice husk, etc. Energy refers to a variety of plants to provide energy, plants, usually herbaceous energy crops, including, oil crops, extraction of hydrocarbons and other types of plants and aquatic plants.(3) of domestic sewage and industrial organic wastewater sewage mainly by urban residents, commerce and services a variety of drainage component, such as cooling water, shower drain, toilet drain, laundry drain, kitchen drain, waste water and so on. Industrial organic wastewater is mainly alcohol, wine, sugar, food, pharmaceutical, paper making industry and slaughter of the production process of the wastewater, etc., which are rich in organic matter.(4) municipal solid waste, municipal solid waste mainly by the urban living garbage, commercial garbage service and a small amount of construction waste and other solid waste composition. Its composition is complex, affected by the average standard of living of local residents, the energy consumption structure, urban construction, natural conditions, customs and traditions as well as seasonal changes and other factors.

Geneology Files


At some stage in documenting your family tree, it is important to start in search of files of your family. They speak on behalf of those who came before you! The important issue is how to find these. The obvious place is to search online for facts. Some internet sites have popped up throughout the years just as people look to previous times to find out their roots. Here are some to see:RootswebExactlty what can you expect to find on these web sites? Birth together with death certificates, marriage licenses together with divorce decrees, military services records and in some cases tax information in many cases. And a second spot to look for these records is in your home town or perhaps the hometowns of your family members.Public offices, clearks and even courts make the perfect spot to check for [url=]geneology records[/url].You might also prefer to check with local newspapers for obituaries. All of these small summaries could maintain evidence to spouses, children, parents along with siblings of your ancestors. Churches may possibly as well own significant information to peice together your past. Baptisms, christenings, first communions, and so on., may be written about and even on file and also offer valuable dates and also names.The superior news is that you are gathering up information and also adding it to your collection of data so that others won’t really need to reinvent the wheel! And with the web pages, you can select to scan virtually any records you find together with upload them onto the web to share with others in their family search.

Physical and Chemical Methods of Liquid Dispersion


The techniques that are used in the dispersion of powders in both aqueous and non-aqueous media are quite similar. Dispersants aid wetting and stabilization of a suspension can be ionic (anionicor cationic) or non-ionic. However, concentrations of dispersants must be low. Otherwise, their properties are reduced or even inverted (i.e., cause aggregation or flocculation). In dispersing a powder in a non-aqueous medium, it is critical to select an organic solvent that is a good diluent as well as dispersant, although there are many organic dispersant aids. Aqueous surfactants are primarily responsible for reducing surface tension, hence aiding in the dispersion of powders in aqueous systems. The first task in dispersing a dry powder is the wetting of the sample with diluentor dispersant, if needed. Gentle spatulation of the resulting paste prior to addition of diluent further aids the dispersion process. Once the diluent is added, a sample of the slurry can be placed on a slide for a microscopic evaluation of the effectiveness of dispersion. Providing that the sample is well dispersed, the use of a magnetic stir bar is suggested to keep the sample fully dispersed, so are presentative sample can be drawn for analysis while stirring is in progress. Physical Methods of Liquid Dispersion Chemical Methods of Liquid Dispersion Wetting agents:Used to lower surface tension (e.g., hydrophobicity) between diluent (typically water) and particle (usually non-ionic agent). Surfactants: “Surface active agents” increase the surface charge of the particles in order to cause them to repel one another so that they remain properly dispersed while in the suspension.Types of surfactants include: Stabilization by Surface Charge Common Ions Multiple-charged Ions Surfactant Ions which charge the surface Reference –