Pharmalot blogs back

According to The Scientist, Ed Silverman’s Pharmalot blog is back, with a new home at The Wall Street Journal. Earlier this year (January 2), the blog was shut down by its former parent company, UBM Canon, which shuttered a handful of websites including PharmaLive.com, on which Pharmalot once resided.

In a June 3 post, Silverman said he will continue to cover the pharmaceutical and biotech industries as he has in the past. “And the subject matter will continue to touch on many topical bases—successes and failures as told by executives and patients; R&D challenges; patent skirmishes; marketing wars; government oversight; the use of social media and pricing tussles with payers, to name a few,” he wrote.

Posted by Tim Sandle

New microscope in development

Scientists rely heavily on incubators and microscopes. With this in mind the Fraunhofer Institute for Biomedical Engineering IBMT has come up with a novel solution that combines the functions of both these tools in a compact and extremely small-scale system. It is ideally suited for time-lapse examination over a number of weeks and for automatic observation of cell cultures. The incubator microscope is no bigger than a soda can and costs 30 times less than buying an incubator and a microscope separately. It will be on display for the first time at MEDTEC in Stuttgart.

Cultivating human and animal cells requires parameters such as temperature and humidity to be specified with absolute precision and maintained at an even level over long periods of time. Time-lapse observation over a period of some weeks can be particularly valuable, since a lot happens in that time in terms of cell reproduction and differentiation. Until now, the usual technique to make these sorts of observations has been to use small incubators in combination with conventional microscopes. This takes up about one square meter of space, making operating several such systems alongside each other an inefficient process. There is a need for innovative solutions that will significantly reduce the space needed and the costs involved -- without compromising the quality of the cultivation and of the microscope images recorded.

The new technology includes a small-scale incubation chamber and control electronics to ensure defined cell culture parameters. Cells grow on the floor of the miniaturized incubation chamber on a thin, replaceable glass plate and are supplied with a constant stream of nutrients. The only parameters that need to be kept constant within the incubator are the temperature and the nutrient supply flow rate. All in all, the small-scale incubator microscope is extremely good value and allows for many units to be operated in parallel in a very compact space. And despite its space-saving design, the system yields images that are almost as good as those of the big microscopes.

Posted by Tim Sandle

Culturing microorganisms

For over 100 years microbiologists have known, to their great consternation, that in any given environment, at least 90% of all microbes are unculturable. In the last few decades, we have developed molecular tools to see these microbes in the environment and determine their presences and number, but we still cannot bring them into culture. There are all sorts of ideas for why this might be true. Many of these microbes may be slow growing, and the fast growing microbes easily outpace them in laboratory medium. Maybe the media we use is "too rich" for many microbes and we need to create media with more dilute nutrients to capture these shy microbes. Maybe the metabolic demands of these microbes were too difficult to replicate in the laboratory and many of them will not grow. Whatever the reason, as of right now, we are nearly blind when it come to these unculturable microbes.

A landmark paper was published a year ago in Applied and Environmental Microbiology. Buerger et. al created a simple, elegant experiment to try to capture the slow-growing bacteria. Sediment from the ocean shore of Massachusetts Bay was diluted and then dispensed into wells of a microtiter plate such that each well received only 1 microbe per well. The growth medium used was 0.1x LB medium, a dilution of a common, rich medium. The plates was carefully wrapped and placed in a humidified chamber for 18 months. Yes, that is a 1.5 year experiment! Periodically the plates were checked for growth and any well showing growth was then characterized.

The expected result was that the slow-growing microbes would arrive later and the number of novel species isolated would increase as the length of the incubation increased. This would fit the hypothesis that the slow growers were being out competed. To their surprise, this was not the case. As the experiment went on, the percentage of novel species did not increase, but stayed remarkably similar. In addition, bacteria isolated by this technique did not grown much slower than microbes that have been cultivated for many years. Buerger et al. hypothesize that cells in the environment may be in a dormant state, and only randomly emerge from this state and grow. This "Scout Hypothesis" would explain the results that they were seeing. They also did a similar experiment on a soil sample and observed similar results

The implication of this experiment is that it should be possible to isolate and characterize many more unculturable species using very simple, and inexpensive techniques. Given enough experimentation, scientists may be able to culture a much larger proportion of the species present in an environment.
Posted by Paustian

Mobile genetic elements in bacteria and archaea

Researchers uncover a group of mobile genetic elements in bacteria and archaea encoding a Cas enzyme. Transposons are stretches of DNA that can hop to different sites in the genome and are commonly found in many types of organisms. In a study published in BMC Biology, researchers described a new type of transposon-like element in bacteria and archaea that encodes a Cas enzyme—well appreciated for its role in the CRISPR/Cas adaptive immune system in prokaryotes—which it in turn requires for integrating into a new genomic home.

As an immune response, CRISPR/Cas works by targeting and chopping up foreign DNA, and labs around the globe have adapted it for genomic editing purposes using the enzyme Cas9.

Casposons are now the second family of transposons—aside from a group present in eukaryotic genomes—known to be self-synthesizing, meaning that they code for their own DNA polymerase involved in replication.

Posted by Tim Sandle

Bacillus cereus infections (update)

Publication of the main findings from the PHE and MHRA investigation into the Bacillus cereus outbreak in the U.K. (issued by Public Health England).

Public Health England (PHE) and the Medicines and Healthcare products Regulatory Agency (MHRA) are in the final stages of their investigations into the outbreak of Bacillus cereus in the implicated intravenous liquid (Total Parenteral Nutrition, TPN).

Since the last update on 12 June 2014, a further case has been identified and the total number of cases linked to this investigation is 23 (19 confirmed and 4 possible cases). This baby has sadly died and our thoughts are with the family. This is the third confirmed case to have died and all 3 cases have been reported to the coroner.

The baby most recently identified received the implicated batch of TPN from 27 May 2014 but did not immediately develop sepsis so did not fit the case definition of the outbreak at that time. However, recent microbiological tests have shown the presence of the outbreak strain.

The strain of Bacillus cereus identified in the 19 cases confirmed as infected, has also since been identified in environmental samples collected from the day of manufacture (27 May 2014), located within the particular sterile area at ITH Pharma where the specific TPN supplies were manufactured. These specific TPN supplies were recalled by the MHRA on 4 June 2014.

Bacillus cereus is a common bacteria found widely in the environment in dust, soil and vegetation. Bacillus cereus produces very hardy spores, which make it persistent in the environment. Under certain conditions, the bacteria produces a number of toxins which can cause illness.

There is sufficient scientific evidence to indicate that the contamination was introduced into these specific TPN supplies during manufacture in a particular sterile manufacturing area at ITH Pharma on 27 May 2014 and MHRA’s investigations of the production process of TPN have found no evidence to suggest that individual ingredients, components or materials used were the cause of the contamination.

The MHRA has inspected ITH Pharma’s manufacturing facility and undertaken a rigorous and thorough review of the manufacturing processes and conditions within which the specific TPN supplies were manufactured. Based on the information obtained, there is sufficient evidence to indicate an isolated incident. Appropriate immediate action has since been taken at ITH Pharma’s facility to avoid a recurrence. The MHRA continues to allow TPN, a critical product, to be manufactured at ITH Pharma and therefore be supplied to patients.

Unopened supplies of the contaminated TPN (manufactured on 27 May 2014 at ITH Pharma) were collected from a few hospitals and these have been confirmed to contain the same strain of bacteria. Other tests on unopened TPN products manufactured by ITH Pharma after 27 May 2014 have all been clear of the bacteria.

A public health investigation that compared 18 confirmed cases with a comparison group of babies who did not have the outbreak strain of Bacillus cereus demonstrated a highly significant association between receiving TPN manufactured on 27 May 2014 and being infected by the outbreak strain.
Professor Mike Catchpole, PHE Incident Director, said:

"There are still some elements of our investigation that need finalising but the main findings have all pointed towards there being a single incident that occurred on one day and was associated with the illness seen in the babies. We are reassured that this was a very rare occurrence as we have not seen this particular strain of bacteria in any product made since that day and there has been no further illness."

Gerald Heddell, the MHRA’s Director of Inspection, Enforcement and Standards, said:

"At this stage, our investigation has provided sufficient evidence to indicate that the contamination was introduced into the specific Total Parenteral Nutrition (TPN) supplies during manufacture in a particular sterile manufacturing area at ITH Pharma on the 27 May 2014.
There is no evidence to suggest that individual ingredients, components or materials used for the manufacture of TPN on 27 May 2014 were the cause of the contamination. However, what we do know from our investigation is that the strain of Bacillus cereus which infected the babies has also been identified at ITH Pharma’s manufacturing facility and within some of the unopened TPN supplies manufactured on the 27 May 2014. 

From our investigation to date, we continue to believe this was an isolated incident and that appropriate immediate action has been taken at ITH Pharma’s facility to avoid a recurrence. Therefore we are allowing this critical product to be supplied to patients while our investigation continues."

Posted by Tim Sandle

The Top 66 Aseptic Processing Regulations (IVT)

The Institute of Validation Technology (IVT) have posted an informative blog outlining a vast range of regulations and guidances relating to aseptic processing.

Aseptic processing during the manufacturer of pharmaceuticals, medical devices, and combination products is coming under increasing scrutiny over the last few years. From 2004 to 2010, three quarters of drug product recalls involved sterile drug products, and of these sterile product recalls, approximately 80% were due to lack of sterility assurance. The manufacturing of sterile drug products has consistently remained challenging, and industry is always seeking ways to improve and remain compliant with global regulations.

To view the list, go to IVT

Posted by Tim Sandle

Keeping your health and safety documents up to date, things to remember

Running a business isn’t easy and you might often feel like there simply aren’t enough hours in the day for you to work through all of your tasks. Inevitably, this means certain jobs will get pushed back. However, one of the issues that should never slip to the bottom of your to-do list is safety.

If you don’t keep on top of risk management, the consequences could be disastrous for both your workers and your company overall. With this in mind, it’s vital that you keep your safety documents up to date and do so in an ethical and environmentally friendly way.

Important documents

If you’re unsure which health and safety documents your firm needs, you can turn to the Health and Safety Executive for information or enlist the help of consultants at specialist firms like Phoenix Health & Safety.

One example of a document you’re legally required to create if you employ five or more members of staff is a health and safety policy. These consist of three key sections, namely a statement of intent, details of organisational responsibilities and arrangements for how your firm will achieve its safety aims.

Under UK health and safety laws, these documents must be regularly reviewed and revised, and the changes must be brought to the attention of all workers.

You’ll also need written health and safety risk assessments. These documents identify any hazards that exist in the workplace, the people who may be in danger and the level of risk involved. They also contain suitable measures to control the dangers.

Circumstances change

Health and safety policies, risk assessments and other similar resources are not one off documents that can be completed and then left untouched indefinitely. The fact is, dangers in the workplace change. Staff members come and go, new equipment is introduced and working practices evolve. In addition, safety regulations change over time.

This means it’s vital that you update your health and safety documents on a regular basis.

The risks if you let things slide

Letting safety issues slide is simply not an option. If you do, you risk potentially devastating consequences for your staff members. In the worst cases, your personnel may suffer serious or even fatal injuries.

Meanwhile, if your safety management procedures are discovered to be inadequate, you may find yourself subject to long and costly legal proceedings, which could spell disaster for your bottom line. There is also possible reputational damage to consider.

Environmental factors

The ethical and environmental factors that surround keeping your documentation up to date are also very important, the amount of paper wasted through the replication of documents is huge, it is therefore recommended that you keep a digital copy of all of your health and safety document and make sure that these are amendable, this saves on paper and other filing resources. The setup of digital signatures, digital receipts or online terms and conditions means that you can have accurate, official date at your fingertips.

Help is at hand

You might decide that you are capable of keeping all your health and safety documentation up to date, and there is also the option of involving one or more of your workers in this process. However, if you don’t feel confident when it comes to this aspect of your business, it could pay off to look for help from a third-party provider.

By seeking assistance from specialist consultants, you can ensure these tasks are completed to the relevant standard and, because of this, you can enjoy peace of mind. In addition, you stand to free up more of your time to focus on other issues.

Posted by Tim Sandle

Guideline on the selection of sterilisation processes for drug products

The European Medicines Agency (EMA) has proposed to withdraw the Guideline CPMP/QWP/155/96 "Note for Guidance on Development Pharmaceutics" and to develop a new guideline which will describe the decision tree for the selection of sterilisation methods. The latter is currently available as annex (CPMP(QWP/054(98).

The new document will apply to human and veterinary medicinal products. At the moment, there has been no planned proposal to withdraw the veterinary development pharmaceutics guideline (EMEA/CVMP/315/98).

With the new guideline, the following aspects are recommended to be taken into consideration:

• Specifying conditions when aseptic processing could be accepted
• Requirements for justification of the choice of sterilisation method
• Possible combination with terminal processes to provide a limited sterilisation assurance level (= reduction of bio burden)
• Gas sterilisation processes
• Sterilisation of medicinal products with a very short shelf-life
• Revision of the decision tree
• Necessity of biological validation of terminal sterilisation processes

For further details, see: "Establishment of aguideline on the selection of sterilisation processes for drug products".

Thanks to the ECA for notification of this change.

Posted by Tim Sandle

Biochemicals from the Bacterial Factory

Oil as a natural resource is becoming scarcer and more expensive and there is a need to look at eco-friendly ways of extracting it, thereby reducing CO2 emissions. White biotechnology offers a solution: scientists are now using microorganisms such as bacteria to generate substances for the production of polymers. The advantage is that these miniature biochemical factories run on renewable resources or agricultural waste converting it into valuable chemicals.

For further details, see Process Worldwide

Posted by Tim Sandle

Are forest fungi symbiotic?

Symbiotic relationships between trees and the mycorrhyzae that grow in their roots may not be as mutually beneficial as previously thought. Recent experiments had brought into a question a long-held theory of biology: that the fungi or mycorrhizae that grow on tree roots work with trees in a symbiotic relationship that is beneficial for both the fungi and the trees, providing needed nutrients to both parties. But in contrast to the current paradigm, the new research shows that they may be the cause rather than the cure for the nutrient scarcity.

A new study, led by IIASA Ecosystems Services and Management researcher Oskar Franklin in collaboration with the Swedish University of Agricultural Sciences, used a theoretical model to explain the new experimental findings, by simulating the interaction between individual fungus and plant. It suggests that since each organism competes with others in trading nutrients such as carbon and nitrogen, the system as a whole may function more like a capitalistic market economy than a cooperative symbiotic relationship. The competition among trees makes them export excessive amounts of carbon to the fungi, which seize a lot of soil nutrients.

Understanding boreal forest nutrient cycles is incredibly important for modeling climate change, because it influences how much carbon dioxide these regions can absorb, as well as how they are influenced by the increasing concentrations of greenhouse gases in the atmosphere.

For further details, see the following paper:

Oskar Franklin, Torgny Näsholm, Peter Högberg, Mona N. Högberg. Forests trapped in nitrogen limitation - an ecological market perspective on ectomycorrhizal symbiosis. New Phytologist, 2014; DOI: 10.1111/nph.12840

Posted by Tim Sandle

The Importance of Biological Safety

Biological safety is about ensuring that individuals, products and the environment as a whole are all kept as safe as possible from hazardous biological materials. Not only are more and more stringent rules being placed on businesses dealing with biological matter, but the public perception of how companies deal with such matter has also never been as important for the continued success of an organisation as it is today.

Ensuring that employees and technicians have the right training and the right tools may not only make a difference to the success of a project but also to the safety of those within the laboratory environment, the reputation of an organisation and even the chances of them seeing significant profits or attracting suitable funding in the future.

Safety products

Biological safety products such as the laminar flow cabinets available from companies like CAS are designed to protect against the most common threats posed by biological agents. Not only will such cabinets protect the individuals carrying out any work with potentially dangerous biological materials, but they will also help to preserve the integrity of the materials themselves, ensuring that important work is not ruined by contamination.

In turn, the importance of biological safety is not just about safeguarding individuals in the immediate future. Instead, by improving the safety of the materials being used in experiments or research, the right focus on safety may also simply ensure the best possible results and help to make certain that important scientific advances are made sooner rather than later, and that simple mistakes do not ruin the chances of the desired results being achieved. As such, safety is also about protecting the world as a whole through bringing about important scientific breakthroughs.

Sourcing biological safety equipment

When it comes to biological safety, ‘one-size-fits-all’ will not apply. As in any scientific realm, the importance of altering approaches based on given variables is vital and when it comes to choosing the likes of biological safety cabinets, it will be important to choose a solution that will more than adequately satisfy your needs.

However, choosing the right classification of cabinet is not the only thing that will affect the suitability of your solution. To keep your air clean, your environment uncontaminated and your personnel safe, it will be wise to research companies before you buy to ensure that you source such products from a reputable firm with a proven record of success. Furthermore, you may also then wish to speak to the very same specialist companies to make sure that the safety products you choose are indeed the most suitable ones for your own unique needs and processes, as well as the materials you need to handle and contain.

Training

As well as safety solutions such as laminar flow cabinets, biosafety courses will also be important, and even those well-versed in best laboratory practices may find that undertaking certain training courses can be helpful, keeping them completely up to date with current legislation and making sure that they also are able to learn more about the way in which new technologies could be shaping safety within the laboratory. However, for the most part, training will simply be necessary to make certain that individuals know how to keep themselves, their work and the environment as safe as possible as the biological world around them evolves.
Posted by Tim Sandle

Urine is not sterile

Urine is not sterile, even before it comes out of you and gets contaminated by your skin. Bacteria are present at low levels in the urine of healthy people not suffering from a urinary tract infection, Evann Hilt of Loyola University of Chicago reported May 18 at a conference of the American Society for Microbiology.

The urinary microbiota was shown to contain: a total of 217 bacterial isolates from 77 different genera were isolated from OAB patients, while 66 bacterial isolates from 33 different genera were isolated from control patients. Organisms isolated solely from OAB patient urines included Actinobaculum schaalii, Aerococcus urinae, Arthrobacter cumminsii, and Oligella urethralis; each has been reported to cause UTI.

Researchers are starting to explore what bacteria make up the normal bladder community and whether a change in that community might trigger urinary problems.

Posted by Tim Sandle

Solid Dosage and Excipients e-book (free)

Pharmaceutical Technology’s Solid Dosage and Excipients e-book examines emerging trends in the formulation and manufacture of solid dosage drugs, as well as the role of excipients in enhancing the functionality of these drug forms.

Topics include:

• Applying QbD to Process Optimization
• Roundtable: Excipients for Controlled-Release Drugs
• Excipients for Generic Formulations
• Continuous Tablet Manufacturing
• Modular Systems for Oral
• Solid-Dosage Manufacturing
• Particle-Size Distribution via
• Dry Granulation

The e-book format includes interactive formats and links to additional resources.

For details, see Pharm Tech.

Posted by Tim Sandle

Helicobacter cinaedi infection promotes atherosclerosis

Atherosclerosis is a chronic inflammatory disease, mainly driven by both innate and adaptive immune responses. However, the initiating factor in this chronic inflammation in atherosclerotic tissues remains poorly characterized.

A recent article published in Nature reported that Helicobacter cinaedi infection significantly enhanced atherosclerosis in hyperlipidaemic mice, with macrophage-driven proinflammatory responses involved. (2014 Sci Rep. 4, 4680). 

The abstract reads:

“Helicobacter cinaedi is the most common enterohepatic Helicobacter species that causes bacteremia in humans, but its pathogenicity is unclear. Here, we investigated the possible association of H. cinaedi with atherosclerosis in vivo and in vitro. We found that H. cinaedi infection significantly enhanced atherosclerosis in hyperlipidaemic mice. Aortic root lesions in infected mice showed increased accumulation of neutrophils and F4/80(+) foam cells, which was due, at least partly, to bacteria-mediated increased expression of proinflammatory genes. Although infection was asymptomatic, detection of cytolethal distending toxin RNA of H. cinaedi indicated aorta infection. H. cinaedi infection altered expression of cholesterol receptors and transporters in cultured macrophages and caused foam cell formation. Also, infection induced differentiation of THP-1 monocytes. These data provide the first evidence of a pathogenic role of H. cinaedi in atherosclerosis in experimental models, thereby justifying additional investigations of the possible role of enterohepatic Helicobacter spp. in atherosclerosis and cardiovascular disease. ”

Posted by Tim Sandle

Kawasaki disease is wind-borne

Cases of the debilitating childhood disease in Japan are likely caused by toxins that float in from China’s farmlands, a study finds.

Kawasaki disease, the number-one cause of acquired heart disease in children in industrialized countries, may be caused by toxins that arrive with seasonal winds, according to a study published in PNAS. A team led by Xavier Rodó, a climate scientist at the Institut Català de Ciències del Clima (IC3) in Barcelona, Spain, studied outbreaks of the disease in Japan from 1979 to 2010. Comparing that information to wind patterns, the researchers narrowed the source of the disease to farmland in northeastern China.

The team also found Candida fungus in air samples taken from winds blowing from northeastern China.

Kawasaki disease is most common in children under five and causes a rash and an often uncontrollable fever. The disease was first identified in Japan in 1961, but its cause remains a mystery. The highest incidence of Kawasaki disease is in Japan, which reports more than 12,000 cases annually. In the U.S., 5,000 to 6,000 cases are reported every year.

Posted by Tim Sandle