Wednesday, 31 October 2018

FDA - Dissolution Testing and Acceptance Criteria

FDA has issued a new guidance document: “Dissolution Testing and Acceptance Criteria for Immediate-Release Solid Oral Dosage Form Drug Products Containing High Solubility Drug Substances Guidance for Industry”.

This guidance is developed to provide manufacturers with recommendations for submission of new drug applications (NDAs), investigational new drug applications (INDs), or abbreviated new drug applications (ANDAs), as appropriate, for orally administered immediate release (IR) drug products that contain highly soluble drug substances. The guidance is intended to describe when a standard release test and criteria may be used in lieu of extensive method development and acceptance criteria-setting exercises.


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 30 October 2018

NIBSC experts will be discussing how control materials are relevant

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Antibacterial Drug Discovery: Some Assembly Required

Our limited understanding of the molecular basis for compound entry into and efflux out of Gram-negative bacteria is now recognized as a key bottleneck for the rational discovery of novel antibacterial compounds. Traditional, large-scale biochemical or target-agnostic phenotypic antibacterial screening efforts have, as a result, not been very fruitful. A main driver of this knowledge gap has been the historical lack of predictive cellular assays, tools, and models that provide structure–activity relationships to inform optimization of compound accumulation. A variety of recent approaches has recently been described to address this conundrum. This Perspective explores these approaches and considers ways in which their integration could successfully redirect antibacterial drug discovery efforts.

This is an interesting research paper:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 29 October 2018

Medical data on COPD

Chronic obstructive pulmonary disease (COPD) mainly includes three related respiratory diseases, namely chronic bronchitis, chronic asthma and pulmonary emphysema. In each of the aforementioned conditions, there is a degree of chronic obstruction in the passage of airflow through the airways and through the lungs. This obstruction is generally permanent and may be progressive in the course of years.

A new paper of interest the abstract reads:

“The aim of the present study is to highlight the seasonal cases diagnosed with chronic obstructive pulmonary disease, present in the specialized medical service with acute symptomatology. In order to establish a more accurate diagnosis, besides the specialized medical examination, paraclinical investigations such as standard pulmonary radiography and spirometry, were used.”


Chesca, A., Sandle, T., Akhayeva, A.S., and Marchenko, A. B. (2018) Medical data on COPD, Medicine and Ecology, 86 (1), pp82-85

For details, please contact Tim Sandle

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 28 October 2018

New approach to fighting antibiotic resistant bacteria

One of the most pressing concerns on the planet is the issue of multi-drug resistance bacteria and the risk these organisms pose to human health. One of the ways to address this could stem from a new research project.

The project is being undertaken at the University of Houston, where two researchers secured a $3.5 million grant (over a five-year period) to build novel technologies to ascertain which are the best chemical combinations to kill the most resistant bacteria, in the form of antibiotics. The grant comes from the U.S. National Institute of Allergy and Infectious Diseases.
Antimicrobial resistance is about the ability of a microorganism to resist the action of antimicrobial drugs. The phrase multi-drug resistance is when an organism is resistant to one or more chemicals. While this state of resistance can occur in nature, the major threat to human health arises with known human pathogens acquiring resistance, a more common method is through gene transfer. Here, genes causing resistance can be transferred between different strains of microorganism. Where this occurs in the healthcare setting, where patients are more vulnerable, concerns arise.
In recent decades the proportion of organisms becoming multi-drug resistance has increased. Much of this arises from the mis-prescribing of antibiotics.
Commenting on the new research project, lead researcher Professor Vincent Tam explains: “People are dying, there’s no question about that. And it’s because bacteria - time and again - have come up with ways to fight back against the antibiotics we are throwing at them and survive.”
The microbiologist adds: “In the war of people versus bacteria, bacteria are winning.” To combat this Professor Tam explains, combining antibiotics is a common practice. However, the complication arises from selecting the correct combination.
What is needed is a faster and more robust process to ensure that the correct chemical combinations are selected. This is the basis of the new research. For this the researchers are collaborating with the commercial company BacterioScan.
The intention is to build a rapid diagnostic device that is capable of testing bacterial responses to various drug combinations. The aim is for a medical professional to place bacterial samples into the device. The device will then assess bacterial growth in the presence of different antibiotics. The data will be captured digitally and analysed, with the clinician provided with the optimal antibiotic combination.
Testing will begin with a selection of hospital pathogens, including Pseudomonas aeruginosaAcinetobacter baumannii; and Klebsiella pneumoniae. The aim is to pinpoint the different structural classes of antibiotics which will be effective against the organisms at different sites.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 27 October 2018

Advanced Technologies are Tackling the Global Lyme Epidemic

More than 300,000 new cases of Lyme disease, the most common tick-borne illness in the United States, are diagnosed each year. In a new interview with CMRubinWorld, Dr. Brian Fallon, Director of the Lyme and Tick-Borne Diseases Research Center at the Columbia University Irving Medical Center reveals that despite the challenges to find a cure for this complex, debilitating disease, precision medicine and biotechnology are accelerating the discovery of new tools with which doctors will be able to diagnose it and treat patients.

In an authoritative new book, Columbia University Medical Center physicians Brian Fallon and Jennifer Sotsky explain why there is much cause for optimism. “Through rapid genetic sequencing, scientists can identify many different strains of Borrelia burgdorferi (causative agent of Lyme disease) as well as new tick-borne microbial infections, such as Borrelia miyamotoi, Borrelia mayonii, and the Heartland virus,” says Fallon. The discovery of these new microbes inside ticks has significantly helped researchers since it “provides a starting point for the study of pathogenesis, vaccine development, and treatment.” Fallon notes that researchers have also been able to screen thousands of drugs to determine which have the ability to destroy Borrelia.

Read the full article here

Brian Fallon, MD, MPH is the Director of the Lyme and Tick-Borne Diseases Research Center at the Columbia University Irving Medical Center and the author with Jennifer Sotsky of Conquering Lyme Disease: Science Bridges the Great Divide, published in 2018 by Columbia University Press.

CMRubinWorld’s award-winning series, The Global Search for Education, brings together distinguished thought leaders in education and innovation from around the world to explore the key learning issues faced by most nations. The series has become a highly visible platform for global discourse on 21st century learning, offering a diverse range of innovative ideas which are presented by the series founder, C. M. Rubin, together with the world’s leading thinkers.

For more information on CMRubinWorld

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 26 October 2018

European Pharmacopeia to update chapter of F concept for heat sterilization

The change affects chapter 5.1.5 “Application of the F concepts to heat sterilisation – 50105”.

This chapter has been revised in order to add a definition of FH for dry heat sterilization and how to calculate it. It is common practice to determine FH values for dry heat processes in a similar manner to F0 for steam sterilization.

Heat sterilisation can be differentiated into 2 types, according to the water or steam content during the sterilisation phase: moist heat sterilisation using saturated steam or water heated to the sterilisation temperature; and dry heat sterilisation using hot air with a moisture content so low as to have an insignificant biological activity.

The new chapter is expected to come into force early in 2019.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 25 October 2018

A New Take on Fighting Multi-Drug Resistant Bacteria

Two UH researchers have won a five-year, $3.5 million grant from the National Institute of Allergy and Infectious Diseases to develop technology that will quickly suggest the most promising combinations of antibiotics to kill certain resistant bacteria. According to the Centers for Disease Control, “Antibiotic resistance is one of the most urgent threats to the public’s health.”

“People are dying, there’s no question about that. And it’s because bacteria - time and again - have come up with ways to fight back against the antibiotics we are throwing at them and survive,” said College of Pharmacy professor Vincent Tam who, along with Michael Nikolaou, professor of chemical and biomolecular engineering, intends to even the score with bacteria by optimizing clinical use of antibiotic combinations to combat resistance.

“In the war of people versus bacteria, bacteria are winning,” said Tam. It’s not just because they reproduce every 20 minutes and outnumber all of us (estimates propose five million trillion-trillion bacteria), they also have become more sophisticated and resistant. Thirty years ago, the chances of bacteria being resistant to ampicillin, a common antibiotic, was 5 percent. Today it is more than 50 percent.

Combining antibiotics has emerged as a typical practice to treat infections caused by virulent strains of bacteria resistant to a single antibiotic. But quickly choosing the correct combination is tricky. For instance, the antibiotic prescribed for a wound infection is not the same one prescribed for strep throat or a myriad of other infections.

“A robust method to guide rational selection of effective antibiotic combinations is crucial to help prevent returning to the pre-antibiotic era of untreatable infections,” said Tam. The team is working with an external company, BacterioScan, to develop a rapid diagnostic device that will test bacterial responses to several drug combinations. Clinicians will place bacteria samples in the device, a box, which will monitor bacterial growth in the presence of different antibiotics and will automatically process collected data to spit out predictions of the best combinations in short order.

“I don’t have the time and luxury to take days, if not weeks, to figure this out when a patient is dying. The device we are developing will only take hours,” said Tam, who envisions these monitors in every hospital lab. The box will deliver a raw signal, or string of numbers, that Nikolaou’s algorithms will interpret to deliver a predicted ranking system of the best combinations.

Initial testing will include bacteria P. aeruginosa, which cause pneumonia, A. baumannii which cause urinary tract infections and meningitis, and the superbug Klebsiella pneumoniae, which can cause all three illnesses and others. They will test different structural classes of antibiotics to hit the bugs at different sites.

Since bacteria are different from person-to-person, this approach is a personalized solution to a problem that cannot be solved with a one-size-fits all prescription.

“It is tailor made and customized to deliver results for a specific bacterium for a specific patient,” said Tam.
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 24 October 2018

Strategies for Building a Flexible Clinical Supply Chain to Meet Modern Challenges

A new eBook from Pharmaceutical Technology – ‘Strategies for Building a Flexible Clinical Supply Chain to Meet Modern Challenges’

Proactively planning for a supply chain is vital for giving clinical sponsors improved visibility and control over their clinical supplies. It also helps improve information and provide opportunities for making adjustments throughout a study. Strategies for Building a Flexible Clinical Supply Chain to Meet Modern Challenges addresses this critical issue, offering insight into:
  • Strategic opportunities in clinical research 
  • Survey results: past, present, and future of clinical trials 
  • Global clinical trial challenges 
  • Importance of planning for clinical supply 
  • Comparator sourcing 
For detail see:

Download the eBook »

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 23 October 2018

FDA - Labeling for Biosimilar Products

FDA has issued a new guidance document ‘Labeling for Biosimilar Products’.

FDA - Labeling for Biosimilar Products. The goal of a biosimilar product development program is to demonstrate biosimilarity between the proposed product and the reference product — not to independently establish safety and effectiveness of the proposed product. A demonstration of biosimilarity means, among other things, that FDA has determined that there are no clinically meaningful differences between the proposed product and the reference product in terms of safety, purity, and potency.

The introduction to the report reads:

“This guidance is intended to help applicants develop draft labeling for proposed biosimilar products for submission in an application under section 351(k) of the Public Health Service Act (PHS Act) (42 U.S.C. 262(k)). The recommendations for prescription drug labeling in this guidance pertain only to the prescribing information (commonly referred to as the package insert), except for certain recommendations in section V pertaining to FDA-approved patient labeling (e.g., Patient Information, Medication Guide, and Instructions for Use).2 This guidance does not provide specific labeling recommendations for interchangeable products (see section VIII of this guidance). In general, FDA’s guidance documents do not establish legally enforceable responsibilities. Instead, guidances describe the Agency’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required.”


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 22 October 2018

Importance of Microbial Contamination Control

Tim Sandle has written an editorial of the special edition of the Journal of GxP Compliance, dedicated to pharmaceutical microbiology.

This special edition captures some of the current themes and issues relating to pharmaceutical microbiology and contamination control, and many of the points required to develop a control strategy.

The importance of microbiological control in relation to the manufacture of pharmaceutical and healthcare products is the theme of this special compilation for IVT Network. The articles selected highlight the twin themes of maintaining control through the assessment of risk and the use of sound, scientific methods to assess risk. This latter area includes the use of rapid and alternative methods.

While microbiology plays a role in drug development, through the application of biotechnology (including the development of anti-infective agents and with the manufacture of pharmaceutical products), a considerable part of the role of the pharmaceutical microbiologist is with protecting pharmaceutical and healthcare products from spoilage by microorganisms and thus protecting patients and consumers. With both sterile and non-sterile products, the effects can range from discoloration to the potential for fatality.

The reference is:

Sandle, T. (2018) Editorial: Importance of Microbial Contamination Control, SPECIAL EDITION: Essential Microbiology for GXP Compliance: 3-6 - 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 21 October 2018

Bacteria used as cell factories to produce biofuels

A new technique for manipulating small cell structures for use in a range of biotechnical applications including the production of biofuels and vaccines has been developed by a team of scientists led by the University of Kent.

The researchers did this by creating an improved system to allow for the synthesis of nano-reactors within cells that can be used to help convert sugar into fuel. The same technology can be used to coat nano-particles with proteins so that they can be used to generate vaccines.

The researchers redesigned and engineered the tiny bacterial cellular structures -- known as organelles -- so they can be more easily manipulated and deployed to turn bacteria into 'cell factories'.

The organelles, which are approximately 100 nm in diameter and known as bacterial microcompartments (BMCs), naturally house specific metabolic pathways, essentially a linked series of chemical reactions. Although BMCs have huge potential in the area of biotechnology, a key obstacle to their utilisation is the difficulty of targeting new pathways and processes into the BMC in a controllable fashion.

To address this problem, researchers at Kent's School of Biosciences redesigned a key surface component of the BMC that enables them to not only internalise proteins within the BMC but also display them on the surface of the organelle.

To achieve this the Kent researchers, working with others from University College London, the University of Bristol and Queen Mary University of London, utilised a pair of interacting peptides, developed at Bristol, to target proteins to these intracellular organelles. This technology facilitated the display of proteins on the surface of BMCs.

The use of synthetic biology then allowed the researchers to remodel one of the components of the BMC shell which in turn allowed them to use the same technology to internalise proteins within BMCs.


Matthew J. Lee, Judith Mantell, Ian R. Brown, Jordan M. Fletcher, Paul Verkade, Richard W. Pickersgill, Derek N. Woolfson, Stefanie Frank, Martin J. Warren. De novo targeting to the cytoplasmic and luminal side of bacterial microcompartments. Nature Communications, 2018; 9 (1) DOI: 10.1038/s41467-018-05922-x

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 20 October 2018

Test detects disease-carrying mosquitoes, presence of biopesticide

A new diagnostic tool has been developed by researchers at The University of Texas at Austin that can easily, quickly and cheaply identify whether a mosquito belongs to the species that carries dangerous diseases such as Zika virus, dengue, chikungunya or yellow fever. It can also determine whether the bug has come into contact with a mosquito-control strategy known as Wolbachia.

"Many of these diseases are spreading in areas where they weren't common before," said Sanchita Bhadra, a research associate in the Department of Molecular Biosciences and first author on the paper. "Having surveillance is important in conjunction with any kind of outbreak, and this method allows a rapid test in the field."

The tool uses a smartphone camera, a small 3D-printed box and a simple chemical test to show whether a dead mosquito belongs to the Aedes aegypti species. Aedes aegypti carries Zika and other devastating viruses that afflict an estimated 100 million people worldwide each year. The species also is closely linked to the tripling of cases of mosquito-borne diseases in the United States since 2004.

The research appears in the journal PLOS Neglected Tropical Diseases.

The tool developed by scientists and students at UT Austin also detects the presence of a biopesticide called Wolbachia, a type of bacteria that keeps mosquitoes from spreading diseases. In countries around the world and in 20 U.S. states where the Aedes aegypti mosquito is found, scientists working in public health agencies have started to infect mosquitoes with Wolbachia by introducing the bacteria into a local mosquito population to help curb transmission of viruses.

Because mosquitoes show no outward signs of having the bacteria -- and because existing diagnostic tests are hard to read, expensive and logistically cumbersome -- the new tool represents a significant step forward for those hoping to monitor the effectiveness of Wolbachia.

"This test can happen without involving a lot of staff and equipment to make sure Wolbachia is effective and spreading as anticipated," Bhadra said.

Public health groups trap and kill mosquitoes routinely in conjunction with monitoring efforts, but existing technology requires a complex process to extract nucleic acid from inside mosquitoes, often after they have been dead for days and have started to decay, leading to greater expense and the possibility of more errors in lab tests than the new technology.

The new diagnostic tool uses a smartphone's camera and a simple test that can be done anywhere. It tests mosquitoes' nucleic acid without requiring a complicated process to remove it. Officially known as a loop-mediated isothermal amplification and oligonucleotide strand displacement, or LAMP OSD, the probe delivers a simple yes-or-no readout on a cellphone, with accuracy of greater than 97 percent.

In addition to the tests to detect mosquito species and Wolbachia, the team also is exploring use of the technology to easily identify whether trapped mosquitoes are carrying Zika, dengue and other pathogens.


Sanchita Bhadra, Timothy E. Riedel, Miguel A. SaldaƱa, Shivanand Hegde, Nicole Pederson, Grant L. Hughes, Andrew D. Ellington. Direct nucleic acid analysis of mosquitoes for high fidelity species identification and detection of Wolbachia using a cellphone. PLOS Neglected Tropical Diseases, 2018; 12 (8): e0006671 DOI: 10.1371/journal.pntd.0006671

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 19 October 2018

New compound effective against drug-resistant pathogens

Researchers from North Carolina State University have synthesized an analog of lipoxazolidinone A, a small molecule that is effective against drug-resistant bacteria such as MRSA. This molecule, a new synthetic compound inspired by a natural product, could be a useful chemical tool for studying other Gram-positive infections and may have implications for future drug creation.

Lipoxazolidinone A is a natural product which had been previously isolated from bacteria living in marine sediments. It is a secondary metabolite -- a small molecule produced by the bacteria that isn't key to its survival but is produced for a secondary purpose, like defense. When lipoxazolidinone A was initially isolated, researchers noted that it seemed effective against Gram-positive bacteria, like MRSA.

NC State chemist Joshua Pierce aimed to confirm those original findings and understand how the molecule's structure correlated to its function; in short, he wanted to recreate the molecule to see what portions were directly responsible for its anti-microbial properties and then potentially improve upon that structure.

Pierce, along with current NC State graduate student Kaylib Robinson and former students Jonathan Mills and Troy Zehnder, used novel chemical tools to synthesize lipoxazolidinone A in the lab. They were able to confirm that its chemical structure matched what the initial researchers had indicated, then they worked to identify the portion of the molecule that was responsible for the activity against Gram-positive bacteria. Their result was a compound with improved potency, JJM-35.

They tested JJM-35 against a panel of resistant and non-resistant bacteria. When tested against MRSA in-vitro, they found that the synthesized molecule was up to 50 times more effective than the natural product against several bacterial strains. Additionally, they found that the molecule was often more effective against resistant bacterial strains than it was against nonresistant strains.


Jonathan Mills, Kaylib Robinson, Troy Zehnder, Joshua G Pierce. Synthesis and Biological Evaluation of the Antimicrobial Natural Product Lipoxazolidinone AAngewandte Chemie International Edition, 2018; DOI: 10.1002/anie.201805078

Posted by Dr. Tim Sandle

Thursday, 18 October 2018

EU GMP Annex 2

Annex 2 to EU GMP has recently been updated. This is: “Annex 2 Manufacture of Biological active substances and Medicinal Products for Human Use.” This came into effect on 26th June 2018.

Annex 2 of the GMP Guide has been revised as a consequence of the adoption of the Guidelines on Good Manufacturing Practice specific to Advanced Therapy Medicinal Products pursuant to Article 5 of Regulation (EC) 1394/2007 of the European Parliament and of the Council of 13 November 2007 on advanced therapy medicinal products and amending Directive 2001/83/EC and Regulation (EC) No 726/2004.

Please note Annex 2 is no longer applicable to Advanced Therapy Medicinal Products to which applies the Commission guideline on Good Manufacturing Practice for Advanced Therapy Medicinal Products, published in Part IV of Eudralex Volume 4 and operational as of 22 May 2018.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 17 October 2018

SimpliciTB Clinical Trial Launched

TB Alliance has initiated a pivotal clinical trial, SimpliciTB (pronounced: sim-plis-i-tee-bee), that will evaluate whether a new four-drug regimen can treat most types of tuberculosis (TB) including multidrug-resistant TB (MDR-TB) more quickly and effectively than currently-available treatments. The first patients have been enrolled at the National Center for Tuberculosis and Lung Disease in Tbilisi, Georgia. SimpliciTB is expected to enroll 450 people with TB, including up to 150 with MDR-TB* across at least 26 centers in 10 countries in Africa, Asia, Europe and Latin America.

SimpliciTB will test the efficacy of a four-month treatment with the BPaMZ regimen, consisting of the drugs bedaquiline, pretomanid, moxifloxacin and pyrazinamide, in people with drug-sensitive TB. Outcomes will be compared against the standard six-month treatment regimen of isoniazid, rifampicin, pyrazinamide and ethambutol (HRZE), to determine whether BPaMZ may be able to shorten the duration of therapy for drug-sensitive TB by a third.

The trial will also assess BPaMZ’s potential to treat MDR-TB in six months. Currently, treatment for drug-resistant TB is extremely complicated, expensive, and lengthy, involving a wide variety of medicines that have debilitating side-effects, can include injectable drugs, and are administered for nine months to two years or longer. Today, people with MDR-TB often go untreated, and of those who do receive treatment only about half are cured.

“As resistance to current TB treatments continues to grow, we need to introduce all-oral drug regimens that can treat every person with TB in six months or less, regardless of their resistance profile,” said Mel Spigelman, president and CEO of TB Alliance. “If proven successful in SimpliciTB, the BPaMZ regimen would represent a major step toward this goal.”

The BPaMZ regimen was previously studied in the Phase 2b study called NC-005, in which people with MDR-TB who were treated with the BPaMZ regimen cleared TB bacteria from their lungs up to three times faster than drug-sensitive TB patients treated with the standard (HRZE) treatment. NC-005 was an eight-week trial conducted at 10 sites across Uganda, South Africa and Tanzania. SimpliciTB builds on these results, testing BPaMZ over a longer duration, in more people and across more sites, and against both drug-sensitive and MDR-TB.

According to the World Health Organization’s most recent Global Tuberculosis Report, there is growing resistance to available drugs, which means the disease is becoming more deadly and difficult to treat. WHO estimates that in 2016 there were 600,000 new cases with resistance to rifampicin–the most effective first-line drug—of which 490,000 had MDR-TB.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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