FDA approves new antibiotic

A second new drug to treat methicillin-resistant Staphylococcus aureus (MRSA) has been approved under the U.S. Food and Drug Administration's (FDA) new fast-track incentive program.

The first of the new antibiotics released under the scheme is called Dalvance. This is an intravenous drug that can treat skin and soft tissue infections, and the launch was reported on by Digital Journal. Dalvance is intended to treat acute bacterial skin and skin structure infections.

News of the second medication was released at the end of June 2014. The drug is known as Sivextro or tedizolid phosphate. The antibiotic has been approved for intravenous or oral use to treat severe MRSA. According to U.S. News and Health Report, the drug was clinically tested in more than 1,300 adults with serious skin infections. Here Sivextro was found to be as effective as linezolid, an antibiotic currently in use that has a similar mechanism of action.

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What is being done about antibiotic resistance? SPECIAL

E. coli evolves antibiotic tolerance

Antibiotics win public’s vote for Longitude Prize

Both antibiotics were developed and approved through FDA’s new Generating Antibiotic Incentives Now (GAIN) program, which offers incentives such as extended exclusivity to manufacturers of new antibiotics.

Under this scheme, the New York Times reports that at least two antibiotics may soon follow. Cubist Pharmaceuticals, the manufacturers of Sivextro, have also reported that the FDA are reviewing ceftozolone, an antibiotic candidate that aims to treat complicated urinary tract and intra-abdominal infections. Second, a clinical trial by researchers at Duke University tested the antibiotic oritavancin to treat acute skin infections. The initial results appear encouraging.

Posted by Tim Sandle

What is being done about antibiotic resistance?

Humans face the very real risk of a future without antibiotics. The implications of this are that life expectancy could fall due to people dying from diseases that are readily treatable today. This is the warning issued in a new paper by Tim Sandle.

Over the past year, various reports have been issued which highlight the problem of antibiotic resistant bacteria and the risks to human health. While this is worrying for the public, what are scientists actually trying to do about it?

Writing in an editorial for the journal Microbiology & Infectious Diseases, Digital Journalist Tim Sandle has outlined some of the different types of research that are taking place.

Though many governments are placing restrictions on antibiotic use, this is too little, too late. The current situation has made the quest for new antibiotics and antibiotic alternatives a matter of great importance.

Examples highlighted by Dr. Sandle include:

The use of pulsed light

Scientists have successfully used technology that disinfects food products to destroy antibiotic resistant bacteria around the site of burns. When someone becomes badly burnt, standard burn treatment involves removal of burned tissue, skin grafts, and the application of antiseptic and antimicrobial dressings to prevent and treat infection. Here antibiotic-resistant bacteria present a major risk to the patient, partly due to the increasing failure of many types of antibiotics. Pulsed electrical fields (PEFs) have been used for decades to preserve food by destroying bacteria. It works by destroying the bacterial membrane. To explore the technology’s application of burns, scientists applied a multidrug resistant strain of a bacterium to small third-degree burns that had been made on the backs of anesthetized mice. The results are promising.

Screening the world's resources of valuable molecules

This is a slow process requiring the testing of new molecules as potential antibiotics. One main centre of analysis is the laboratory of Kenneth Keiler (from Penn State University, USA). The research team here has examined 663,000 different molecules against a strain of Escherichia coli bacteria. The researchers have monitored how the chemicals affect the growth and survival of the bacterium. From this, forty-six potential chemicals have been selected. It is a long process, but some encouraging results are emerging.

New bacteria killing chemical

A new antibacterial agent, termed as Peptide-conjugated phosphorodiamidate morpholino oligomers (PPMO) is being examined. The chemical has the ability to silence the expression of specific genes within bacterial cells, thereby stopping them from gorwing.

Working on a new broad spectrum antibiotic

There is a good candidate drug called SQ109. This compound attacks the tuberculosis bacterium. Scientist are currently looking to see how the drug can be modified to target other pathogens from yeast to malaria. By targeting multiple pathways, the scientists are of the opinion that this reduces the probability of pathogens becoming resistant.

Adding silver to existing antibiotics

Taking another approach, some scientists contend that adding silver to existing antibiotics can increase their effectiveness. Here researchers have explained the cellular processes by which the precious metal weakens bacteria and makes them more susceptible to antibiotics.

Although these different research paths are interesting, the menacing threat of emerging and developing antibiotic resistance by a growing number of different types of bacteria presents a serious problem for society.

Posted by Tim Sandle

E. coli evolves antibiotic tolerance

Subject to repeated exposure to the antibiotic ampicillin, populations of Escherichia coli quickly evolve tolerance for the drug, springing back to life once antibiotic treatment has stopped, according to a new study.

A new, worrying report has emerged in relation to the battle against antibiotic resistance. Researchers repeatedly exposed cultures of E. coli to high concentrations of ampicillin. Within as few as 10 cycles, the team found that some bacteria had survived the antibiotic treatments by lengthening the period of time they stay dormant.

Ampicillin is an oral antibiotic useful for the treatment of a number of bacterial infections. It is effective for ear infections and respiratory infections. It is also sometimes used for the treatment of urinary tract infections, meningitis, and salmonella infections.

Scientists have noted over the past few years that resistance to ampicillin is increasingly common among the bacteria responsible for such infections. Now E. coli can be added to the list. Traditionally, E. coli has been resistant to ampicillin. Or, rather, in this case, "antibiotic tolerance." The study highlights the importance of antibiotic tolerance, which allows bacteria to survive even high levels of antibiotics by remaining dormant. As to the reason for this, by exploring the genetic basis of this adaptation, the researchers identified three genes that seemed to play a functional role in antibiotic tolerance.

Escherichia coli is a Gram-negative, rod-shaped bacterium that normally inhabits the intestines of humans and animals. Not all strains of E. coli are pathogenic, but ones that are contribute to one of the leading causes of foodborne illnesses.

The study was conducted at The Hebrew University of Jerusalem in Israel, and the findings have been published in the journal Nature. The paper is titled "Optimization of lag time underlies antibiotic tolerance in evolved bacterial populations."

Posted by Tim Sandle

Reviewing fungal classification

Fungi that digest wood in novel ways could fuel new avenues of research on cellulosic ethanol, and suggest a need to move beyond traditional classification systems.

Fungi that digest wood are typically categorized as white rots, which degrade both lignin and cellulose, or brown rots, which only have enzymes that act on cellulose. But two newly sequenced species are capable of digesting lignin, even though they lack the enzymes typically found in white rots, according to a study published in PNAS.

The species, Botryobasidium botryosum and Jaapia argillacea, appeared to be white-rot fungi based on the microscopic patterns they created in decomposing wood. “But at the molecular level, we found that the key enzymes considered markers of white-rot fungi were missing,” said Igor Grigoriev of the US Department of Energy (DOE) Joint Genome Institute (JGI) in Walnut Creek, California, who led the work.

The results suggest “a continuum rather than a dichotomy between the white-rot and brown-rot modes of wood decay,” and highlight the need for a more nuanced categorization of rot types, according to the authors. Identifying the decay mechanisms in these new species could also have practical applications in the production of cellulosic biofuels, said Grigoriev.

“There was a lot of suspicion within the scientific community that the decay mechanisms wouldn’t be as straightforward as they’re currently classified, but the data wasn’t quite there,” said fungal biologist Dan Eastwood of Swansea University in Wales, who was not involved with the work. “This study brings more genomes to the point where we are plugging important gaps to say it’s more complicated than [just two kinds of rot].”

Eastwood likened the structure of wood to that of reinforced concrete, where lignin forms the concrete, and cellulose the iron rods that run through and support the structure. Brown-rot fungi digest only the cellulose, leaving behind a dark-colored, brittle mass of lignin. White-rot fungi often digest lignin first, leaving behind long strands of cellulose in a fibrous mass. The two kinds of decay create different porous structures in wood.

For the present study, Grigoriev and his colleagues compared the genomes of 33 basidiomycetes, a group which encompasses most wood-decaying species, including four newly-sequenced species. A phylogenetic analysis of the plant-biomass-decomposing enzymes used by these organisms showed that two of the new species were closely related to a model white-rot fungus, Phanerochaete chrysosporium, and could decompose crystalline cellulose even though they lacked the lignin peroxidases typically used by white rots.

The microscopic structures created by the two rots are “a result of these processes,” Grigoriev explained. “The lignin peroxidases were the key distinction,” he said. “Now we see the different phenotypes even with the lack of these enzymes.”

The work “lays a lot of significance only to two exceptional fungi, so I would not totally abandon the dichotomic separation of wood rotting fungi,” said microbiologist Annele Hatakka, a professor at the University of Helsinki, Finland, who was not involved in the study.

Hattaka agreed that the term “white rot” should be used only to describe fungi that degrade all the components of wood—lignin, cellulose, hemicellulose, and other polymers. But she highlighted a need for more genome data on common white rots. “We have too few genomes of the most typical white-rot fungi,” she wrote in an e-mail. “More than 90 [percent] of wood-decaying fungi are traditional white rots. We should have many more common white-rot fungal genomes, for example to see the significance of laccase, which was once considered the most typical characteristic of white-rot fungi.”

The wood-decay mechanisms used by these new species also reveal their evolutionary history. In a 2012 Science paper, the researchers showed that a white-rot species was likely the common ancestor of both rots; brown rot fungi then branched out from this ancestor on several separate occasions, the authors proposed.

“The evolution that allowed an organism to break down wood for the first time, only occurred once, as far as we know,” said Eastwood. “Very few things can break down wood.”

Understanding the enzymatic and non-enzymatic mechanisms that these fungi use to decompose lignin could inform biofuel industries, according to Grigoriev. Manufacturing ethanol from cellulose frequently requires lignocellulose digestion, a step that remains a major challenge. Bio-refineries to convert lignocellulose to fuels were not commercially viable as of a 2011 report from the National Academies of Sciences.

“As we move towards a bio-based economy, it is important to understand biological processes that convert plant biomass into biofuels,” said Grigoriev. “We’re trying to use genomics to learn to build the machinery for a bio-based economy.”

R. Riley et al., “Extensive sampling of basidiomycete genomes demonstrates inadequacy of the white-rot/brown-rot paradigm for wood decay fungi,” PNAS, doi:10.1073/pnas.1400592111, 2014.

Source: The Scientist

The Wound Microbiome

Knowing precisely the microbes present in a wound could greatly aid in the prevention and treatment of infections. This is especially important when dealing with the severe injuries that soldiers can suffer in combat.

Tending to injured soldiers in combat is “among the most complex and challenging seen in modern medicine,”  according to Eric Elster, a professor and chairman of the Uniformed Services University’s surgery department, who has discussed the subject in an interview with the Los Angeles Times.

In the July 2014 issue of the Journal of Clinical Microbiology, Elster and his colleagues report on a method for rapidly detecting the microbiota of U.S. service members hurt in combat. Their paper is titled "Microbial profiling of combat wound infection through detection microarray and next-generation sequencing".

For the study, the researchers analyzed tissue samples taken from 44 soldiers who had been wounded in Iraq or Afghanistan and subsequently evacuated. The most common microbe they detected, present in about a quarter of the wounds, was one called Acinetobacter baumannii. Interestingly, the bacteria they found to be associated with wounds that healed (as opposed to those that would not) are known to colonize the gut. These included Bacteroides, E. coli, Salmonella, and Enterobacter. The research also showed that wound healing was not particularly influenced by the total number of bacteria (the 'bioburden'); the biggest factor were the types of bacteria present. 

“This may reflect changes in immunoregulation and remodeling of the wound, where a microenvironment that is progressing toward healing is an amenable niche to distinct classes of bacteria from an environment that is immunologically distant from successful resolution,” the authors wrote in their report.

Outlining thus further Elster told the LA Times: “Studies such as this one will allow us to better understand the interaction between the body and pathogens, and develop new treatment strategies."

Posted by Tim Sandle

Antimicrobial resistance

European Medicines Agency releases draft advice on the impact on public health and animal health of the use of antibiotics in animals

The European Medicines Agency (EMA) has published draft recommendations today in response to a request from the European Commission related to the impact on public health and animal health of the use of antibiotics in animals.

The European Commission made this four-part request for advice in April 2013 as part of its action plan against the rising threats from antimicrobial resistance(AMR). The emergence and steady increase in the occurrence of bacteria that are resistant to multiple antibiotics has become a global public-health threat due to the lack of therapeutic options to treat certain infections in man.

Foe details see EMA

Posted by Tim Sandle

Study on the incidence of certain neoplastic diseases

Because of the increased incidence of malignant pathology in individuals, prevention measures must be practically applied by screening programmes. Such measures are considered useful to increase citizens’ life quality, otherwise serious consequences for health could entail. In this context, this study comparatively presents the incidence of types of malignant pathologies found in the last quarter of 2012 and in the first quarter of 2013, in the specialized service, according to the information collated within a database. The study was made possible through collaboration with the specialty medical staff.

To evaluate the incidence of the malignant pathology across the period, the study was carried out by analyzing the types of malignant pathologies, taking into consideration the residence environment of the patients, sex, newly found and diagnosed cases, together with the cases already on records. The conclusion was that women are the most affected group, with those residing in urban areas showing the highest level of incidence. This data is of importance to the healthcare sector, especially when considering that neoplastic pathology has a harmful prognostic on both health and quality of life.

This is the basis of a paper written by researchers from the Transilvania University of Braşov in collaboration with Tim Sandle.

The reference is:

Chesca, A., Sandle, T. and Gyurka, G.A. (2014) Study on the incidence of certain neoplastic diseases, Acta Medica Transilvanica, 2 (2): 168 – 172

To request a copy of the paper, please contact Tim Sandle.

Posted by Tim Sandle

FDA guidance for the development of nanotechnology products

FDA Issues Guidance to Support the Responsible Development of Nanotechnology Products.

Three final guidances and one draft guidance were issued by the U.S. Food and Drug Administration providing greater regulatory clarity for industry on the use of nanotechnology in FDA-regulated products.

One final guidance addresses the agency’s overall approach for all products that it regulates, while the two additional final guidances and the new draft guidance provide specific guidance for the areas of foods, cosmetics and food for animals, respectively.

The guidances are:

Final Guidance for Industry: Considering Whether an FDA-Regulated Product Involves the Application of Nanotechnology

The guidance outlines overarching considerations for all FDA-regulated products, identifying points to consider when determining whether a product involves the use of nanotechnology. It is intended to help industry and others identify when they should consider potential implications for regulatory status, safety, effectiveness or public health impact that may arise with the application of nanotechnology in FDA-regulated products.Final Guidance for Industry: Safety of Nanomaterials in Cosmetics

Theguidance describes the FDA’s current thinking on the safety assessment of nanomaterials when used in cosmetic products and encourages manufacturers to consult with the FDA on test methods and data needed to support the substantiation of a product’s safety.

Final Guidance for Industry: Assessing the Effects of Significant Manufacturing Process Changes, Including Emerging Technologies, on the Safety and Regulatory Status of Food Ingredients and Food Contact Substances, Including Food Ingredients that are Color Additives

The guidance alerts manufacturers to the potential impact of any significant manufacturing process change, including changes involving nanotechnology, on the safety and regulatory status of food substances. This guidance also describes considerations for determining whether a significant manufacturing process change for a food substance already in the market affects the identity, safety, or regulatory status of the food substance, potentially warranting a regulatory submission to the FDA.

Draft Guidance for Industry: Use of Nanomaterials in Food for Animals

This draft guidance addresses issues related to the use of nanotechnology in food ingredients intended for use in food for animals. Public comments on this draft guidance are requested by September 10, 2014.

For further information, see Pharmaceutical Processing

Posted by Tim Sandle

'Hidden diversity' of mouth bacteria

A new computational method for analyzing bacterial communities has uncovered closely related, previously indistinguishable bacteria living in different parts of the human mouth. The technique, developed by Marine Biological Laboratory (MBL) scientists, provides high taxonomic resolution of bacterial communities and has the capacity to improve the understanding of microbial communities in health and disease.

An important step in understanding the role of oral bacteria in health and disease is to discover how many different kinds live in the mouths of healthy people, and exactly where in the mouth they normally live. Using a novel computational method called oligotyping, developed by MBL Assistant Research Scientist A. Murat Eren, scientists analyzed gene sequence data from nine sites in the oral cavity. The data was provided by The Human Microbiome Project (HMP), an effort of the National Institutes of Health that produced a census of bacterial populations from 18 body sites in more than 200 healthy individuals. DNA in these samples was sequenced from the gene in bacteria that encodes ribosomal RNA, called the 16S rRNA gene, or 16S.

To this point, an understanding of the biomedical significance of HMP data has been hindered by limited taxonomic resolution. "Different species of bacteria can have very similar 16S gene sequences, sometimes differing by only a single DNA base in the region that was sequenced, and errors in DNA sequencing can also create differences of one or a few DNA bases," says the study's co-author Jessica Mark Welch, an Assistant Research Scientist at the MBL.

While the HMP data set has been used to identify bacteria broadly, to genus-level groups, it has never been used to identify bacteria more precisely, to the species level. "This genus-level grouping meant that many bacteria with similar DNA, but very different roles in the human microbiome, were lumped together, limiting the usefulness of the data," says Mark Welch. Using oligotyping, Eren, Mark Welch and their colleagues Gary Borisy of the Forsyth Institute and Susan Huse of Brown University re-analyzed the HMP 16S gene data from dental plaque, saliva, and the surfaces of the tongue, cheek, gums, hard palate, tonsils, and throat. They found closely related, but distinct, bacteria living on the tongue, on the gums, and in plaque. For example, bacteria in saliva and in hard palate, tonsils, and throat resembled the tongue bacteria, while bacteria on the cheek were similar to bacteria on the gums.

Bacteria from plaque below the gum-line also were detected on the tonsils, suggesting that the tonsils provide an oxygen-free environment where these bacteria can grow and come into contact with the human immune system. Oligotyping detected kinds of bacteria that differed by as little as a single DNA base in the sequence tag. These differences in the 16S gene did not change the properties of the bacteria, but acted as markers for larger changes elsewhere in the bacterial genome which, the researchers believe, lead to different bacterial properties that make the bacteria prefer one part of the mouth over another.

"These distinct bacteria were present in the data all along, but were indistinguishable because they were so similar to each other hidden in plain sight, and revealed by oligotyping," says Mark Welch. "This method offers a better understanding of the distribution of precisely defined taxa within the mouth, and demonstrates a level of ecological and functional biodiversity not previously recognized. The ability to extract maximum information from sequencing data opens up new possibilities for the analysis of the dynamics of the human oral microbiome." Eren has applied the oligotyping method to improve taxonomic resolution in other bacterial communities, including those from wastewater, from marine sponges, and from ocean water. The researchers say the technique has the capacity to analyze entire microbiomes, discriminate between closely related but distinct taxa and, in combination with habitat analysis, provide deeper insights into the microbial communities in health and disease. "The diversity of naturally occurring bacteria continues to impress us, and our study demonstrates that a comprehensive understanding in microbial ecology through marker genes requires our attention to subtle nucleotide variations," says Eren. "I anticipate that the ecologically important information oligotyping helped us recover from the human oral microbiome will intrigue other investigators to take a second look from their microbiome data sets."

More information: Oligotyping analysis of thehuman oral microbiome, PNAS

Posted by Tim Sandle

Progress on the UK antimicrobial resistance strategy

From: Department of Health and Dr Felicity Harvey CBE, Director General for Public Health.

Antimicrobial resistance (AMR), especially resistance to antibiotics, is a growing problem and there is now a risk that the practice of modern medicine will not be possible in the next 20 years because we have run out of effective antibiotics. I, like Dame Sally Davies, our Chief Medical Officer (CMO), am determined that will not happen, not just for us, but for future generations.

In September 2013, we published the UK Five Year AMR Strategy with the goal of slowing the growth of AMR by taking an integrated approach across human and animal health and the environment at both national and international levels. An early priority has been to agree a set of measures against which we could track progress towards our goal.

The Advisory Committee on Antimicrobial Resistance and Healthcare Associated Infections (ARHAI) and Public Health England (PHE) have worked with us to develop measures which include resistance trends in selected drug-bug combinations and improvements in the quality of prescribing in primary and secondary care.

In November we will publish our first annual progress report and a detailed implementation plan with a focus on deliverables. The annual report will describe progress across the areas that we have identified as the priorities for action in this first phase. These are better data and information, behaviour change, improved diagnostics and new treatments, enhanced research and analysis and stronger international collaboration. We, and our partners, are making good progress in each of these areas.

Progress DH has made

We have undertaken a range of analyses and modelling of the burden and potential impact of AMR on health, the NHS and the consequent economic and social costs to inform the wider programme and help assess the likely effectiveness of potential interventions to reduce AMR. We will be publishing these later this year.

To improve diagnostics we are working with experts including the Chief Scientific Officer at NHSE, Medical Microbiology experts in PHE and academia, National Institute for Health Research (NIHR) and the Medical Research Council (MRC) to establish what is needed on the ground, where there are gaps and how we can make sure that the right tests are available in the right settings across the health system.

Research is crucial to our understanding of the molecular basis of the emergence of spread of AMR, the significance of transmission pathways between the environment, humans, animals and the food supply chain in promoting the transfer of resistance in human and veterinary pathogens to help target our interventions. We also need research to help develop new drugs, alternative therapies and improved diagnostic technologies.

In April, two NIHR Health Protection Research Units, focusing on Health Care Associated Infections and AMR were established, between PHE and academic partners. A new AMR Research Funder’s Forum, led by the MRChas been set up to co-ordinate AMR related research and promote joint action to better understand the relationship between AMR in humans and animals.

The UK has been at the forefront of action internationally working with other governments and global organisations including the World Health Organization (WHO) and the World Organisation for Animal Health (OIE), to drive forward coordinated action at an international level.

I am enormously proud of our achievements on the international stage. Together with Sweden, we have led the development and adoption of a new WHO resolution on AMR. The Resolution provides a mandate for development of a WHO led global action plan by May 2015. We will have a key role in influencing and contributing to the development of the action plan and continuing to support the global movement to tackle AMR.

Progress our partners have made

To provide better data and information, PHE has been working with a wide range of bodies to strengthen our national surveillance programme, improving our ability to monitor trends in resistance and integrate data on how antibiotics are used in hospitals, GP surgeries and other healthcare settings. In September, it will publish its first annual report providing a baseline from which to monitor future trends and assess the impact of our interventions.

PHE is stepping up its work with partners across the human health and social care system, holding a workshop with experts in the summer to develop an integrated plan to deliver system wide change. NHS England, NICE and Health Education England are all supporting work to change behaviours and improve the quality of antibiotic prescribing.

The Veterinary Medicines Directorate of Defra and the Responsible Use of Medicines in Agriculture Alliance (RUMA) are undertaking comprehensive sector engagement activities to consider the issues and share good practice.

Much more to be done

However, I am not complacent and while I recognise the significant achievements on the international front, there is much more that needs to be done to deliver real change nationally to improve our infection prevention and control, better control the use of antibiotics and to support the development of new classes of antibiotics, diagnostics and new treatments.

We already have good support from the Royal Colleges and the Faculty of Public Health. This, together with RUMA’s strategy and action plan, issued in April this year, demonstrate that we in the UK are of one voice and truly working together to tackle this important issue.

We can only achieve the goal of the strategy if we continue to work together in this way. The progress report and action plan we publish in the autumn, will provide more detail about what we have and what we intend to achieve together. I call on you now, professionals, health care workers, academics and industry to keep the fight against AMR as a priority in your organisations and to continue to work with us to make those changes that need to happen to deliver our goal.

A Role for Endotoxin in Alcoholism?

Interesting news from BioDtech:

It has previously been demonstrated that biological effects of alcoholism, including liver disease, are partially due to increased bacterial translocation due to a deterioration of gut integrity.  A recent report from scientists at the University of Massachusetts demonstrates that bacterial-induced inflammation can occur in healthy individuals with single episodes of binge drinking:

Acute Binge Drinking Increases Serum Endotoxin and Bacterial DNALevels in Healthy Individuals

Similarly, another publication from the University of Texas indicated that endotoxin-induced inflammation promotes alcohol consumption:

Activation of Inflammatory Signaling by Lipopolysaccharide Producesa Prolonged Increase of Voluntary Alcohol Intake in Mice

Taken together, these results suggest that a single episode of binge drinking could result in endotoxin-induced inflammation and promote the desire for more alcohol.

Scientists at BioDtech, Inc. have measured previously undetectable levels of endotoxin which could cause activation of the immune system.  BioDtech products are designed to more accurately detect endotoxin and remove it from proteins and DNA.

Posted by Tim Sandle

Pharmacopeial Forum 40 (4) – items of interest

Pharmacopeial Forum 40 (4) – items of interest

Items of interest are:

General chapters

111: Design and Analysis of Biological Assays (Revision proposal target, USP38-NF33 2nd Supplement)

Completely revised after the introduction of four new general chapters pertinent to bioassays.

1223:   Validation of Alternative Microbiological Methods (Revision proposal target, USP38-NF33 2nd Supplement)

This proposed revision provides guidance on the selection and implementation of assay methodologies to serve as alternatives to compendial microbiological methods. The revised chapter describes important steps that should be taken to evaluate candidate alternative methods, to select the analytical technology, and ultimately to qualify the method with actual product. These steps include, but are not limited to, identification of a potentially suitable alternative methodology, demonstration that the method is equivalent and applicable as a replacement for a standard compendial method, development of user specifications for equipment selection, and qualification of the method in the laboratory. In addition, this chapter outlines four distinct options for demonstrating equivalence.

Posted by Tim Sandle

Analytical Framework For Examining The Value Of Antibacterial Products

Antibacterial resistance is a growing global problem. According to the most recent statistics from the Centers for Disease Control and Prevention (CDC), at least 2 million people acquire serious infections with bacteria that are resistant to one or more of antibacterial drugs designed to treat those infections in the United States alone. Of these, approximately 23,000 die as a result of drug-resistant infections. Even though estimates vary widely, the economic cost of antibacterial resistance in the United States could be as high as $20 billion and $35 billion a year in excess direct healthcare costs and lost productivity costs, respectively (U.S. Centers for Disease Control and Prevention, 2013).

Despite the potential of new antibacterial products to reduce the social burden associated with resistant infections, some of the large companies have been exiting the markets for antibacterial drugs and vaccines in recent years and have also failed to respond to the possible social value of opportunities in production of rapid diagnostic products. These market exits have been driven by the most basic of reasons: insufficient return to capital invested in development of these products. Consequently, governments across the globe are looking to identify ways to stimulate the development of antibacterial products.

A study, conducted by Eastern Research Group, Inc. (ERG) under contract to the U.S. Department of Health and Human Services (HHS), Office of the Assistant Secretary for Planning and Evaluation (ASPE) and partly funded by FDA, has been conducted. The develops an analytical decision-tree model framework that can be used to assess the impacts of different possible market incentives on the private and social returns to product development of new antibacterial products (in contrast to those already under development).

To view the study, go to: ERG

Posted by Tim Sandle

Quality Management Systems

The objectives of a Quality Management System are to:

• Set direction and meet customers' expectations
• Improve process control
• Reduce wastage
• Lower costs
• Increase market share
• Facilitate training
• Involve staff
• Raise morale

The basis of a Quality Management System is set out in: ISO/FDIS 9001:2008 — Quality management systems — Requirements.

The adoption of a QMS needs to be a strategic decision of an organisation, and is influenced by varying needs, objectives, the products/services provided, the processes employed and the size and structure of the organisation. A QMS must ensure that the products/services conform to customer needs and expectations, and the objectives of the organisation. Issues to be considered when setting up a QMS include:

• Design and build includes the structure of the quality management system, the process and its
• implementation. It's design must be led by senior managers to suit the needs of the organisation, and this is ideally done using a framework to lead the thinking. Design of the QMS should come from determining the organisation's core processes and well-defined goals and strategies, and be linked to the needs of one or more stakeholders. The process for designing and building the QMS must also be clear, with the quality function playing a key role, but involvement and buy-in to the system must also come from all other functions.
• Deployment and implementation is best achieved using process packages, where each core process is broken down into sub-processes, and described by a combination of documentation, education, training, tools, systems and metrics. Electronic deployment via Intranets is increasingly being used.
• Control of the QMS will depend on the size and complexity of the organisation. ISO is a site-based system, and local audits and reviews are essential even if these are supplemented by central reviews.
• Local control, where possible, is effective, and good practice is found where key stakeholders are documented within the process and where the process owner is allowed to control all of the process. Ideally, process owners/operators are involved in writing procedures.
• Measurement is carried out to determine the effectiveness and efficiency of each process towards attaining its objectives. It should include the contribution of the QMS to the organisation's goals; this could be achieved by measuring the following:
  • Policy definition completeness
  • Coverage of business
  • Reflection of policies
  • Deployment
  • Usage
  • Whether staff find the QMS helpful in their work
  • Speed of change of the QMS
  • Relevance of QMS architecture to the job in hand

A form of scorecard deployed through the organisation down to individual objective level can be employed, and the setting of targets at all levels is vital.

Review of the effectiveness, efficiency and capability of a QMS is vital, and the outcome of these reviews should be communicated to all employees. Reviewing and monitoring should be conducted whether or not improvement activities have achieved their expected outcomes.

Improvement should follow as a result of the review process, with the aim of seeking internal best practice. It is part of the overall improvement activities and an integral part of managing change within the organisation.

An effective QMS must ensure that the organisation has a strong Customer Focus. Customer needs and expectations must be determined and converted into product requirements. Top management have to demonstrate Leadership. Providing unity of purpose through an appropriate quality policy, ensuring that measurable objectives are established, and demonstrating that they are fully committed to developing, sustaining and improving the QMS.

Managers must ensure that there is Involvement of People at all levels in the organisation. This includes ensuring that there is an awareness of the importance of meeting customer requirements and responsibilities in doing this, and people are competent, on the basis of appropriate training and experience.

An effective QMS must be a strategic tool designed to deliver business objectives, and must have, at its core, a Process Approach, with each process transforming one or more inputs to create an output of value to the customer. The key business processes may be supported by procedures and work instructions in those cases where it is judged necessary to rigidly define what rules are to be followed when undertaking a task. Most organisations will have core business processes that define those activities that directly add value to the product or service for the external customer, and supporting processes that are required to maintain the effectiveness of the core processes.

The understanding of the many interrelationships between these processes demands that a Systems Approach to management is adopted. The processes must be thoroughly understood and managed so that the most efficient use is made of available resources, to ensure that the needs of all the stakeholders — customers, employees, shareholders and the community — are met.

Customer satisfaction is a constantly moving entity depending on changes in technology and the market place, so an effective QMS must be in a state of Continual Improvement. For this to be achieved, attention needs to be given to both the voice of the customer - through complaint analysis, opinion surveys and regular contacts – and the voice of the processes – through measurement, monitoring and analysis of both process and product data. This will result in Factual Decision Making.

Each organisation is itself only a link in the chain of a larger raw material process, and for the long term needs of the community and the organisation there needs to be Mutually Beneficial Supplier Relationships.

Audits, reviews and assessments

A good QMS will not function or improve without adequate audits and reviews. Audits are carried out to ensure that actual methods are adhering to the documented procedures, whilst system reviews should be carried out periodically and systematically, to ensure the system achieves the required effect.

There should be a schedule for carrying out audits, with different activities possibly requiring different frequencies. An audit should not be conducted just with the aim of revealing defects or irregularities – they are for establishing the facts rather than finding faults. Audits do indicate necessary improvement and corrective actions, but must also determine if processes are effective and that responsibilities have been correctly assigned. The emphasis on process improvement and enhancing customer satisfaction in the revised standard will require a more thoughtful approach to auditing.

The generic steps involved in an audit are:

• Initiation
  • Scope
  • Frequency
• Preparation
  • Review of documentation
  • The programme
• Working documents
  • Execution
• Opening meeting
  • Examination and evaluation
  • Collecting evidence
  • Observations
• Close the meeting with the auditee
• Report
  • Preparation
  • Content
  • Distribution
  • Completion
  • Report
  • Submission
  • Retention

A quality management system review should take place, possibly once a year, which should cover:

• Results of audits
• Customer feedback
• Process and product conformity
• Status of preventative and corrective actions
• Follow up actions from previous management reviews
• Changes that could effect the QMS
• Recommendations for improvements
• Outputs should include:
• Improvements to the QMS and processes
• Improvements of a product related to customer requirements
• Resource needs

In addition, the procedures for conducting audits and reviews and the results from them should be documented, and also be subject to review. Internal system audits and reviews should be positive and conducted as part of the preventative strategy, and not as a matter of expediency resulting from problems. The assessment of a quality system against a standard or set of requirements by internal audit and review is known as a first-party assessment or approval scheme. If an external customer makes the assessment of a supplier, against either its own, or a national or international, standard, a second-party scheme is in operation. The assessment by an independent organisation, not connected with any contract between the customer and supplier, but acceptable to them both, is an independent third-party assessment scheme.

All managers, not just the staff in the "quality department", need to be fully committed to operating an effective quality management system for all the people within the organisation. The system must be planned to be effective and achieve its objectives in an uncomplicated way. It should also not be static, but be flexible, to enable constant seeking of improvements

Quality Management Review

The object of the Quality Management Review is to provide an overview of the results from the Quality Control and Quality Assurance functions. The review forms part of an organization's Quality Management Systems (as detailed in ISO 9001). The issues covered will vary between different workplaces. However, issues often included issues are results of audits; discussions of follow up items; a review of progress relating to non-compliances and discussions relating to the effectiveness of corrective and preventative action; test and sampling efficiency times; customer complaints; rejects; out of specification results from test data; microbiological contamination issues and trends in relation to processing of product and to the manufacturing environment. Issues of major concern are often considered using risk management techniques.

Data is presented by participants from different departments. The data is normally measured against a target (to allow for effectiveness, efficiency and capability to be measured). This can be relatively straightforward, such as the number of internal audits completed against a target level (such as 95% of audits to be completed to schedule) or more complex when relating to statistical process control charts for laboratory test data.

Participants will include representatives of laboratories, production, process, pharmacy and ward management. Meetings are held either monthly, quarterly or annually (at my workplace, the meetings are held quarterly).

Where problems or upward trends are identified the aim of the meeting is to identify the risk, assign a priority, to agree actions and to track progress. For issues that cannot be satisfactorily dealt with these are referred to senior management. Quality Management Review meetings may sometimes elect to form subgroups to examine specific areas, such as sampling; new processes technologies and so on.

It is important that the outcomes of the Quality Management Review are communicated to all members of staff.

Posted by Tim Sandle

What Are Prions?

A prion is short-hand for proteinaceous infectious particle. Prions are infectious proteins thought to cause disease as viruses do (prions are misfolded, misshapen, proteins). The key difference between a prion and a virus is that prions lack the DNA or RNA that forms the command structure of a virus. Prions have been implicated with a number of diseases, including scrapie, kuru (once called laughing sickness), Creutzfeldt-Jakob disease, and in Bovine Spongiform Encephalopathy (BSE) (the so-termed Mad Cow Disease). Mad-cow disease involves prions which have been passed between cattle by eating feed containing (or contaminated with) brain matter from infected animals, and can then be passed on to humans who eat the similarly contaminated meat of infected cattle. There was an outbreak of this disease in British cattle in the 1980s.

The prion proteins contradict a central tenet of molecular biology: that genes affect proteins, but proteins do not affect DNA. To date, any known disease transmitted by prion is untreatable. Prions attack the nervous system, particularly the brain. Once in an animal's brain cells, proteins near the prions apparently begin to deform and refold themselves to match the defective prion. In sheep, scrapie-infected animals stagger and die as their brains disintegrate. With BSE, humans suffer a hideously similar fate.

Posted by Tim Sandle