Monday, 14 October 2019

Digital Transformation of Pharmaceuticals and Healthcare


As with other sectors of the economy, pharmaceuticals and healthcare is undergoing digital transformation and with some companies this is continuing at a rapid pace as companies attempt to mine the sources of data available.

For those involved with the industry, this means an array of new abbreviations, initialism and acronyms to learn. Terms such as: artificial Intelligence, machine learning, internet-of-things (or the ‘industrial’ internet-of-things -IIOT), blockchain, augmented reality, predictive analytics, big data analytics, Industry 4.0 (or Industry X.0), digital twins, and telehealth are becoming part of the modern manufacturing lexicon.

Tim Sandle has written an new article:

Industry 4.0 is the subset of the fourth industrial revolution and it concerns the digital age and the interconnected manufacturing process, plus design of new products and controlling distribution. The route to get there is through digital transformation; and this process has many journeys, ways of thinking and different technologies, which include those centered on smart manufacturing, such as cyber-physical systems, the internet of things, cloud computing, and artificial intelligence. Central to all of this is data and the value that can be drawn from data, either for gaining real-time metrics about operations, production, inventory control, and quality data; to controlling the supply chain (such as through blockchain, which is a digital ledger); and using data for the purposes of predictive analytics.

The reference is:

Sandle, T. (2019): Digital Transformation of Pharmaceuticals and Healthcare, Institute of Validation Technology Blog, published July 2019.

To access, see: http://www.ivtnetwork.com/article/digital-transformation-pharmaceuticals-and-healthcare

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 13 October 2019

FDA - Biological Product and HCT/P deviation reports annual summary for fiscal year 2018


The U.S. FDA requires reporting of certain deviations and unexpected events in manufacturing in accordance with 21 CFR 600.14, 606.171 or 1271.350(b).  The following manufacturers, who had control over the product when an event associated with manufacturing (deviation or unexpected event) occurred, are required to submit Biological Product Deviation (BPD) reports to the Center for Biologics Evaluation and Research (CBER), if the safety, purity, or potency of a distributed product may be affected.


This annual summary report provides an overview of the reports received by FDA during the fiscal year, including detailed information regarding the number and types of deviation reports received. Each firm responsible for reporting biological product and HCT/P deviations needs to use this information in evaluating their own deviation management program.

The current review can be found here: https://www.fda.gov/media/129692/download

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 12 October 2019

Draft ISO 14644-17 Particle deposition rate applications


A new part of the ISO 14644 series is in development – ‘ISO/DIS 14644-17
Cleanrooms and associated controlled environments -- Part 17: Particle deposition rate applications’.

The standard focuses on particle deposition applications, and covers the missing information in existing documents. This new chapter could be applied in many industries such as assembly of microelectronic like sensors and actuator, displays and batteries, optical devices, space industry, automotive, medical devices, and in processes dealing with microbiological contamination.


The new document can be used as a standard in combination with the existing cleanroom standards (ISO 14644 and ISO 14698), and completes coverage of the range of particles that can cause unwanted surface contamination.

The focus is with the particle deposition rate level (PDRL), which is the particle deposition rate (cumulative number of particles per sqm per hour) times the observed particle size D divided by 10.

See: https://www.iso.org/standard/70606.html

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Analytical Quality by Design (AQbD): questions and answers


The MHRA has issued a feature on the application of Analytical Quality by Design to pharmacopoeial standards.


Analytical Quality by Design (AQbD) takes a structured approach to the development of analytical procedures which are fit for purpose and that consistently deliver results that meet predefined objectives. It achieves this through a detailed understanding of all aspects of the analytical methods performance ensuring adequate control and an ability to react to changes which can affect the quality of results.

Then review takes the form of a Q&A, which can be accessed here: https://mhrainspectorate.blog.gov.uk/2019/08/21/analytical-quality-by-design-aqbd-questions-and-answers/

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 11 October 2019

NIAID Officials Call for Innovative Research on Sexually Transmitted Infections


National Institute of Allergy and Infectious Diseases (NIAID) experts call for a renewed focus on sexually transmitted infections. Rates of gonorrhea, syphilis, and chlamydia are all on the rise, and some STIs are developing resistance to common treatments. In a new perspective piece in The Journal of Infectious Diseases, NIAID officials write that biomedical research establishments must work together to develop better diagnostics, treatments and vaccine candidates for STIs.

The perspective piece was written by NIAID Director Anthony S. Fauci, M.D., Robert W. Eisinger, Ph.D., special assistant for scientific projects in NIAID’s Immediate Office of the Director, and Emily Erbelding, M.D., director of NIAID’s Division of Microbiology and Infectious Diseases. The authors note that a variety of STIs are contributing to the public health crisis as cases of gonorrhea, syphilis, and chlamydia are all on the rise. Left untreated, many STIs can cause serious complications. Congenital syphilis can cause stillbirths and health complications in newborns, and gonorrhea and chlamydia can contribute to life-threatening ectopic pregnancies (when a fertilized egg grows outside the uterus). Gonorrhea and syphilis, which are increasing among men who have sex with men and bisexual men, also are associated with an increased risk for HIV transmission and acquisition. Moreover, increasing antimicrobial resistance will make STIs only more difficult to treat, as many existing drugs will become less effective against the microbes that cause gonorrhea and other STIs.


Unfortunately, the authors note, STI research efforts have not adequately addressed the ongoing spread of these diseases. To address this public health threat, biomedical research programs need to be refocused on developing innovative diagnostics, therapeutics, and vaccines for STIs. Healthcare providers need access to faster, low-cost diagnostics to identify both active and asymptomatic STIs. The STI vaccine pipeline also needs to produce effective new candidate vaccines for syphilis, gonorrhea, and chlamydia. As for STI therapeutics, the authors note that research efforts must focus on drug-drug interactions, toxicities and side effects, while keeping ahead of spreading antimicrobial resistance.

See:  https://www.niaid.nih.gov/news-events/niaid-officials-call-innovative-research-sexually-transmitted-infections?utm_campaign=+39719144&utm_content=&utm_medium=email&utm_source=govdelivery&utm_term

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 10 October 2019

Newly discovered microbe degrades oil to gas


Crude oil and gas naturally escape from the seabed in many places known as "seeps." There, these hydrocarbons move up from source rocks through fractures and sediments towards the surface, where they leak out of the ground and sustain a diversity of densely populated habitats in the dark ocean. A large part of the hydrocarbons, primarily alkanes, is already degraded before it reaches the sediment surface. Even deep down in the sediment, where no oxygen exists, it provides an important energy source for subsurface microorganisms, amongst them some of the so-called archaea.

These archaea were good for many surprises in recent years. Now a study led by scientists from the Max Planck Institute for Marine Microbiology in Bremen, Germany, and the MARUM, Centre for Marine Environmental Sciences, provides environmental information, genomes and first images of a microbe that has the potential to transform long-chain hydrocarbons to methane. Their results are published in the journal mBio.
Splitting oil into methane and carbon dioxide

This microbe, an archaeon named Methanoliparia, transforms the hydrocarbons by a process called alkane disproportionation: It splits the oil into methane (CH4) and carbon dioxide (CO2). Previously, this transformation was thought to require a complex partnership between two kinds of organisms, archaea and bacteria. Here the team from Max Planck Institute for Marine Microbiology and MARUM presents evidence for a different solution.


During a cruise in the Gulf of Mexico, the scientists collected sediment samples from the Chapopote Knoll, an oil and gas seep, 3000 m deep in the ocean. Back in the lab in Bremen, they carried out genomic analyses that revealed that Methanoliparia is equipped with novel enzymes to use the quite unreactive oil without having oxygen at hand.

With the combined enzymatic tools of both relatives, Methanoliparia activates and degrades the oil but forms methane as final product. Moreover, the visualization of the organisms supports the proposed mechanism: Microscopy shows that Methanoliparia cells attach to oil droplets.

Methanogenic microorganisms have been important for the earth's climate through time as their metabolic product, methane, is an important greenhouse gas that is 25 times more potent than carbon dioxide.

See:

Rafael Laso-Pérez, Cedric Hahn, Daan M. van Vliet, Halina E. Tegetmeyer, Florence Schubotz, Nadine T. Smit, Thomas Pape, Heiko Sahling, Gerhard Bohrmann, Antje Boetius, Katrin Knittel, Gunter Wegener. Anaerobic Degradation of Non-Methane Alkanes by “Candidatus Methanoliparia” in Hydrocarbon Seeps of the Gulf of Mexico. mBio, 2019; 10 (4) DOI: 10.1128/mBio.01814-19

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 9 October 2019

E. coli's secret weapon in launching infections


Most types of Escherichia coli are harmless, but the ones that aren't can cause severe life-threatening diarrhea. These problematic bacteria launch infections by inducing intestinal cells to form tiny structures, called pedestals, that anchor the pathogens in place and help the colonies grow.

Microbiologists have described an Achilles heel for disabling pedestal formation. Lab experiments on enteropathogenic and enterohemorrhagic E. Coli (EPEC and EHEC) showed that when the pathogens were prevented from injecting a protein called EspG into intestinal hosts, the hosts were slower and less effective in producing pedestals that fixed the bacteria in place. Further investigations revealed the cellular pathways hijacked by EspG.

The findings can help reveal the mechanics of infection and suggest new avenues of treatment. Worldwide, more than 500,000 children die every year from diarrheal diseases, and pathogenic strains of E. Coli are among the most common causes, according to the World Health Organizations. But treating these infections can be tricky. Using antibiotics to treat a person with EHEC, for example, can trigger the bacteria to release Shiga toxin, which can lead to a life-threatening infection similar to sepsis.

Researchers have long known that pathogenic E. coli injects its host with a variety of proteins, including EspG. Until now, however, those interactions have been linked only to other biochemical functions.

Previously, the researchers studied the effects of EspG on macrophages, and those findings suggested the protein may have an overlooked role in pedestal formation with intestinal hosts.
For the current study, they infected one group of Hap1 cells with wild-type EHEC and EPEC, and infected another with the same types of E. Coli, but lacking the genes responsible for producing EspG. Using fluorescence microscopy, the researchers studied the results. The cells infected by E. Coli lacking EspG took longer to produce pedestals the those by wild-type strains, and what pedestals were produced were shorter.


Follow up experiments revealed that the EspG protein hijacks the host cell by scavenging an active enzyme called PAK. Although previous work has shown a link between EspG and PAK, the new study is the first to connect the two to the formation of pedestals. That connection may help researchers studying other diseases, as well. PAK has been implicated in some cancers, and other studies have shown that some viruses -- including HIV -- can activate it.

See:

Vikash Singh, Anthony Davidson, Peter J. Hume, Vassilis Koronakis. Pathogenic Escherichia coli Hijacks GTPase-Activated p21-Activated Kinase for Actin Pedestal Formation. mBio, 2019; 10 (4) DOI: 10.1128/mBio.01876-19

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 8 October 2019

Killer of algae production - Vampirovibreo chlorellovorus - new DNA analysis

New DNA analysis has found genetic diversity in Vampirovibrio chlorellevorus, complicating efforts to protect algae ponds and the biofuels industry from this destructive pest
New DNA analysis has revealed surprising genetic diversity in a bacterium that poses a persistent threat to the algae biofuels industry. With the evocative name Vampirovibrio chlorellevorus, the predatory pest sucks out the contents of the algae cells (thus the vampire reference) and reduces a productive, thriving, green algae pond to a vat of rotting sludge.

“DNA sequences show what are likely different species, suggesting a much larger diversity in this family than we originally assumed,” said Blake Hovde, a Los Alamos National Laboratory biologist. “That means the treatment for one algae pest might not work for another, which can be a big problem for large-scale algae cultivation in the future.”

The research team sequenced two strains of Vampirovibrio from the same pond. The two samples collected one year apart came from an outdoor algae cultivation system in the Sonoran Desert of Arizona run by University of Arizona collaborators Seth Steichen and Judith Brown. The team sequenced and analyzed the genomes to identify the genes involved in predation, infection and cell death of the valuable Chlorella algae that the bacterium targets.

“Our genomic analyses identified several predicted genes that encode secreted proteins that are potentially involved in pathogenicity, and at least three apparently complete sets of virulence (Vir) genes,” Hovde said. Those genes are characteristic of bacteria that carry out cell invasion.

With Chlorella algae valued as a key source of harvestable biomass for biofuels and bioproducts, it is extremely useful to be able to enhance the fundamental understanding of interactions between a unique bacterial pathogen and its green algal host, Hovde noted. The results of this research have direct relevance to the success of large-scale commercial algal production projects underway to advance U.S. energy security (biofuels) and the production of aquaculture feedstocks and algal-based nutraceuticals.

For future work, the team is following up with a project with the Joint Genome Institute to characterize six more pest genomes from the same family to see if the diversity of these organisms continues to expand, or if the researchers can start categorizing these pests into species groups.

Publication: “Vampirovibrio chlorellavorus draft genome sequence, annotation, and preliminary characterization of pathogenicity determinants“ in Phycological Research, https://doi.org/10.1111/pre.12392
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 7 October 2019

How to switch from ‘bad science’ to ‘good science’ (article)



There are many excellent science studies based on well-designed experiments and which make reasoned claims based on the assembled experimental data. While the majority of scientific findings and papers issued each year offer valid findings and make a contribution to the body of knowledge, there are, unfortunately, many cases of ‘bad science’ out there.

Another concern is that outcomes from science papers are sometimes misinterpreted or they are overly exaggerated by the media. This is perhaps reflective of society increasingly seeking quick answers. The reality of science is that progress is invariably slow, based on incremental findings, and occasional contradictions.

Tim Sandle has written an article looking at bad science, good science together with some tips for writing an effective science article.


This article examines what makes for bad science and how bad science occurs, and then contrasts this with some examples of good science. The article also provides advice on what makes for a good science paper and for those wishing to try their hand at writing a science article, advice as to how to approach this is provided.

The reference is:

Sandle, T. (2019) How to switch ‘bad science’ for ‘good science’? (and what makes for a good science paper and how to approach writing a science article), The Journal (Institute of Science and Technology), Summer 2019, pp14-20

To view a copy, see: https://www.researchgate.net/publication/334598499_How_to_switch_'bad_science'_for_'good_science'

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 6 October 2019

Foodborne pathogen sheltered by harmless bacteria that support biofilm formation


Pathogenic bacteria that stubbornly lurk in some apple-packing facilities may be sheltered and protected by harmless bacteria that are known for their ability to form biofilms, according to Penn State researchers, who suggest the discovery could lead to development of alternative foodborne-pathogen-control strategies.

That was the key finding that emerged from a study of three tree-fruit-packing facilities in the Northeast where contamination with Listeria monocytogenes was a concern. The research, done in collaboration with the apple industry, was an effort to better understand the microbial ecology of food-processing facilities. The ultimate goal is to identify ways to improve pathogen control in the apple supply chain to avoid foodborne disease outbreaks and recalls of apples and apple products.

In the study, researchers sought to understand the composition of microbiota in apple-packing environments and its association with the occurrence of the foodborne pathogen Listeria monocytogenes. Their testing revealed that a packing plant with a significantly higher Listeria monocytogenes occurrence was uniquely dominated by the bacterial family Pseudomonadaceae and the fungal family Dipodascaceae.


Biofilms are a collection of microorganisms that attach to a surface and then secrete a slimy material that slows down the penetration of cleaners and sanitizers. The findings of the research provide insight into the Listeria contamination problem and may lead to researchers and the apple industry getting closer to solving it.

The challenge presented by microbiota possibly sheltering Listeria monocytogenes is not limited to fruit-processing facilities or produce, Penn State researchers suspect.

See:

Xiaoqing Tan, Taejung Chung, Yi Chen, Dumitru Macarisin, Luke LaBorde, Jasna Kovac. The occurrence of Listeria monocytogenes is associated with built environment microbiota in three tree fruit processing facilities. Microbiome, 2019; 7 (1) DOI: 10.1186/s40168-019-0726-2

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 5 October 2019

Why initial UTIs increase susceptibility to further infection


More than 60% of women will experience a urinary tract infection (UTI) at some point in their lives, and about a quarter will get a second such infection within six months, for reasons that have been unclear to health experts.


Now, researchers at Washington University School of Medicine in St. Louis have discovered that an initial infection can set the tone for subsequent infections. In mouse studies, the researchers found that a transient infection triggers a short-lived inflammatory response that rapidly eliminates the bacteria. But if the initial infection lingers for weeks, the inflammation also persists, leading to long-lasting changes to the bladder that prime the immune system to overreact the next time bacteria find their way into the urinary tract, worsening the infection.

To understand why some people are more prone to severe, recurrent infections than others, Hannan and co-senior author Scott J. Hultgren, PhD, the Helen L. Stoever Professor of Molecular Microbiology -- along with co-first authors Lu Yu, PhD, and Valerie O'Brien, PhD, both graduate students when the work was conducted -- infected a strain of genetically identical mice with E. coli, the most common cause of UTIs in people. The strain can have widely divergent responses to bacterial bladder infections. Some eliminate the bacteria within a few days; others develop chronic infections that last for weeks.

The researchers infected these mice with E. coli, monitored them for signs of infection in their urine for four weeks, and then gave them antibiotics. After giving the mice a month to heal, the researchers infected them again. For comparison, they also infected a separate group of mice for the first time.

All the previously infected mice mounted immune responses more rapidly than the mice infected for the first time. The ones that had cleared the infection on their own the first time around did so again, eliminating the bacteria even faster than before. But the mice that failed to clear the infection the first time did much worse, despite the speed of their immune responses. A day after infection, 11 out of 14 had more bacteria in their bladders than they had started with, and many went on to again develop chronic infections that lasted at least four weeks.

The difference lay in an immune molecule called TNF-alpha that coordinates a powerful inflammatory response to infection, the researchers discovered. Both sets of mice turned on TNF-alpha within six hours of infection. But the mice that controlled the infection turned off TNF-alpha again within 24 hours, allowing the inflammation to resolve. In the mice with prolonged initial infections, TNF-alpha stayed on, driving persistent inflammation and triggering a change to the patterns of gene activity in immune cells and the cells of the bladder wall.

To find out, the researchers took mice that had recovered from initial prolonged UTIs and depleted their TNF-alpha before re-infecting them with bacteria. Without TNF-alpha driving excessive inflammation, the mice fared better, significantly reducing the number of bacteria in their bladders within a day of infection.


The findings suggest that targeting TNF-alpha or another aspect of the inflammatory response that causes bladder tissue damage during acute infection may help prevent or alleviate recurrent UTIs, the researchers said.

See:

Lu Yu, Valerie P O'Brien, Jonathan Livny, Denise Dorsey, Nirmalya Bandyopadhyay, Marco Colonna, Michael G Caparon, Elisha DO Roberson, Scott J Hultgren, Thomas J Hannan. Mucosal infection rewires TNFɑ signaling dynamics to skew susceptibility to recurrence. eLife, 2019; 8 DOI: 10.7554/eLife.46677

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 4 October 2019

Network of imaging centers to drive innovation in biological research



Interdisciplinary interactions are essential for driving the innovation pipeline in biological imaging, yet collegial workspaces where they can spring up and mature are lacking in the United States. Last fall, the Marine Biological Laboratory (MBL) convened a National Science Foundation workshop to identify the bottlenecks that stymie innovation in microscopy and imaging, and recommend approaches for transforming how imaging technologies are developed and deployed. The conclusions of the 79 workshop participants are summarized in a Commentary in the August issue of Nature Methods.

"We propose a network of national imaging centers that provide collaborative, interdisciplinary spaces needed for the development, application, and teaching of advanced biological imaging techniques," write the authors and workshop leaders, MBL Fellows Daniel A. Colón-Ramos of Yale University School of Medicine, Patrick La Riviere of the University of Chicago, Hari Shroff of the National Institute of Biomedical Imaging and Bioengineering, and MBL Senior Scientist Rudolf Oldenbourg.

"Creating spaces for co-locating microscopists, computational scientists and biologists, in our experience, is a key and missing ingredient in new and necessary ecosystems of innovation. Sometimes the seeds of innovation have to be planted in the same pot for them to flower and be fruitful," Colón-Ramos says.

For the proposed centers to optimally succeed, they need expert staff scientists who engage in and catalyze collaborations among the major players in the imaging ecosystem, the group concluded. The centers will provide space and expertise not only for teaching existing, high-end imaging techniques, but also for designing and testing new technologies with real-world biological applications and disseminating them promptly to staff and visiting scientists, faculty and students. All can participate in an iterative innovation process, driving discovery while becoming interdisciplinary thinkers and project developers themselves.


As a next step in transforming the vision of national imaging centers into a reality, a follow-up meeting with a variety of funding stakeholders will be scheduled in the spring of 2020. 


Daniel A. Colón-Ramos, Patrick La Riviere, Hari Shroff, Rudolf Oldenbourg. Transforming the development and dissemination of cutting-edge microscopy and computation. Nature Methods, 2019; 16 (8): 667 DOI: 10.1038/s41592-019-0475-y

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 3 October 2019

Third new TB drug developed in over half a century must be affordable


The US Food and Drug Administration (FDA) today approved a combination regimen containing a new drug, pretomanid, for the treatment of extensively drug-resistant tuberculosis (XDR-TB). As the third new drug developed for tuberculosis (TB) in over half a century, and the first to be developed as part of a ready-to-use treatment regimen, pretomanid’s approval represents another potent tool for tackling difficult-to-treat drug-resistant forms of TB. The international medical humanitarian organization Doctors Without Borders/Médecins Sans Frontières (MSF), which provides TB treatment to close to 20,000 people worldwide, stressed that the drug must be made affordable to everyone who needs it, especially considering the substantial taxpayer and philanthropic contributions that went into its development.

News from Médecins Sans Frontières

The three-drug regimen (BPaL: bedaquiline + pretomanid + high-dose linezolid) was approved today for adult patients with XDR-, treatment-intolerant, or nonresponsive multidrug resistant pulmonary TB. This new drug regimen could dramatically shorten treatment length to six months, greatly reduce the number of pills required, and help to increase XDR-TB cure rates from the current abysmal 34 percent. While the new regimen will be shorter and simpler to administer, optimism around BPaL is balanced against the need for intensive monitoring for side effects from the high doses of linezolid required. Separate clinical trials run by MSF and TB Alliance are underway to further evaluate pretomanid-containing regimens to try to identify safer future treatment options.

“Treatment of XDR-TB has been dire ever since this form of the disease was discovered,” said Jay Achar, infectious disease specialist and TB medical advisor at MSF. “Having access to effective treatment regimens will give people hope for a cure and help limit transmission of this deadly bacteria. While safer, simpler regimens are still needed, the shorter treatment duration of this novel regimen is an important step in the right direction.”

Pretomanid was developed by TB Alliance, a not-for-profit organization, funded by governments (including Australia, Germany, the UK, and the US) and philanthropic sources, with the expectation that the organization would hold true to its stated mission, that they are “dedicated to the discovery, development and delivery of better, faster-acting and affordable tuberculosis drugs that are available to those who need them.”

In addition, TB Alliance stands to be granted a priority review voucher (PRV). Under the PRV program, when the FDA approves an eligible neglected disease product—a medicine or vaccine—the developer is awarded a PRV. This voucher can be used to accelerate the FDA review of any of the developer’s drugs or vaccines. Alternatively, the developer can choose to sell their voucher to another entity, as has been done previously for as much as $350 million USD. MSF calls for TB Alliance to use this financial reward to ensure that the drug be registered and made available at an affordable price, faster.

“This newly approved regimen containing pretomanid could be a lifesaver for people with XDR-TB, but it’s not time to celebrate yet,” said Sharonann Lynch, HIV and TB policy advisor for MSF’s Access Campaign. “The approval of this new regimen by the US FDA is just the first step. We now need pretomanid to be registered and available at an affordable price in all countries, prioritizing those with the highest TB burden.”

In April this year, TB Alliance granted the first license to the US pharmaceutical corporation Mylan to manufacture, register, and supply pretomanid. To date, TB Alliance and Mylan have not made the price of pretomanid public. It has been estimated that generic versions of pretomanid could be produced and sold at a profit for between $0.36 USD and $1.14 USD per day. The lowest global prices for the other two drugs in the regimen, bedaquiline and linezolid, already run at around $3 USD per day. People needing this treatment regimen would have to take it for six months, amounting to a total price of $548USD, before considering the additional price of pretomanid. MSF has called for treatment of drug-resistant TB (DR-TB) to be no higher than $500 USD per person for a complete treatment course.

But four months on, neither Mylan nor TB Alliance has made the licensing agreement public, despite calls from civil society for transparency on the terms and conditions that will ultimately impact people’s access to this drug globally. Mylan is expected to bring pretomanid to market by January 2020. However, this is dependent on World Health Organization guidance on using the drug, and on Mylan filing for registration in countries with the highest DR-TB burden.

“TB Alliance and Mylan must not squander this opportunity,” said Lynch. “They must make good on TB Alliance’s mandate to deliver affordable treatment—which is why they received the support of government and philanthropic funding that went into the development of pretomanid and this combination—and provide the drug at an affordable, price because when it comes to people with resistant forms of TB, it’s a matter of life or death.”

Pretomanid is part of the same class of drugs (nitroimidazoles) as delamanid—one of the two other TB drugs approved in the last half century—developed by pharmaceutical corporation Otsuka. Delamanid is fraught with access issues: the drug is patented in many countries until 2023, including in India, and the price of a six-month treatment course remains very high (the lowest global price is $1,700 USD), with many people needing the drug for up to 20 months, making the price much higher. If pretomanid is affordable compared to delamanid, it has the important potential to spark competition and reduce prices for this class of drugs.Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 2 October 2019

FDA - Harmonizing Compendial Standards With Drug Application Approval


Harmonizing Compendial Standards With Drug Application Approval Using the USP Pending Monograph Process  - new FDA Guidance for Industry.


This guidance assists applicants and drug master file (MF) holders in the initiation of either revisions to an existing monograph(s) or development of a new monograph(s) under the United States Pharmacopeial Convention Pending Monograph Process (USP-PMP) during FDA’s evaluation of a drug master file or drug product application.2 This guidance describes the process that allows for the revision of compendial standards that are harmonized with the approved quality and labeling requirements for a drug product application.

See: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/harmonizing-compendial-standards-drug-application-approval-using-usp-pending-monograph-process

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 1 October 2019

Solving a molecular scissors mystery


A Netherlands Cancer Institute team, co-led by Thijn Brummelkamp and Anastassis (Tassos) Perrakis, reported independently, but almost simultaneously with three more groups from all over the world, on the crystal structure and mechanism of a peculiar molecular end-tail of the microtubules that constitute the cell skeleton.

A cell skeleton is made of cables called microtubules. These allow a cell to maintain its shape, move to different places and transport molecules through its interior. Microtubules also play a key role in cell division.

The frequently used cancer therapeutic paclitaxel, aimed at cells that are dividing, specifically acts on microtubules and thereby affects their detyrosination. In addition, detyrosynation of tubulin has been implicated in cardiac dysfunction, correct segregation of chromosomes during mitosis, and mental retardation.

Microtubules are continuously modified to serve different purposes within the cell. For this, their tyrosine tails are cut and put back by different enzymes. After researchers from the Netherlands Cancer Institute and Oncode Institute, in 2017, found the identity of the scissors that remove the tail, an apparent race was launched to solve the next piece of the puzzle: to determine the three dimensional structure of these molecular scissors.

This month the Netherlands Cancer Institute team, co-led by Thijn Brummelkamp and Anastassis (Tassos) Perrakis, independently but almost simultaneously with three more groups from all over the world, are reporting on the crystal structure and mechanism of these peculiar molecular end-tail scissors. Tassos Perrakis: ‘This means that a beautiful consensus is emerging, supported by complementary experiments which together have been constructing an exciting story.’

Athanasios Adamopoulos et al., ‘Crystal structure of the VASH1-SVBP complex, a 2 tubulin tyrosine carboxypeptidase’, Nature Structural & Molecular Biology, 1 July 2019.
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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