On Penicillin

Melvyn Bragg and guests discuss penicillin, discovered by Alexander Fleming in 1928. It is said he noticed some blue-green penicillium mould on an uncovered petri dish at his hospital laboratory, and that this mould had inhibited bacterial growth around it. After further work, Fleming filtered a broth of the mould and called that penicillin, hoping it would be useful as a disinfectant. Howard Florey and Ernst Chain later shared a Nobel Prize in Medicine with Fleming, for their role in developing a way of mass-producing the life-saving drug. Evolutionary theory predicted the risk of resistance from the start and, almost from the beginning of this 'golden age' of antibacterials, scientists have been looking for ways to extend the lifespan of antibiotics.

For further details, see BBC Science.

Posted by Dr. Tim Sandle

New survey on microbiological control of tissues

The European Pharmacopoeia (Ph. Eur.) Commission has decided to elaborate a new general chapter on microbiological control of tissue. The aim of the survey is to gather information from relevant stakeholders to enable the Ph. Eur. experts in charge of the elaboration of this chapter to have a clear vision on the current situation regarding the characteristics of tissue preparations used in Europe and how they are monitored with regard to microbiological control.

To access the survey, see EDQM.

This survey will end on 2nd September 2016.

Posted by Dr. Tim Sandle

Bioprocessing & Sterile Manufacturing

Pharmaceutical Technology's new eBook addresses a range of pressing bioprocessing and sterile manufacturing topics.

Features include a report on accelerated scale-up for vaccine production, a review of the new ISO 1464 Parts 1 and 2 standards for air cleanliness classification, aseptic filling advances, a flexible approach to cleanroom design, a science-driven approach for microbial control, removing genotoxic impurities, regulatory enforcement and drug shortages, and qualification and validation of single-use shipping systems.

For details, see: Pharmtech

Posted by Dr. Tim Sandle

FDA - Product Design to Minimize Medication Errors

The U.S. Food and Drug Administration has produced a new guidance for industry of interest. It is titled “Safety Considerations for Product Design to Minimize Medication Errors.”

The introduction reads:

The recommendations in this guidance apply broadly to the development of drug and biologic products. Accordingly, this guidance is intended for sponsors of investigational new drug applications (INDs); applicants of new drug applications (NDAs), biologics licensing applications (BLAs), abbreviated new drug applications (ANDAs); and manufacturers of prescription drugs marketed without an approved application or over-the-counter (OTC) monograph drugs. This guidance provides a set of principles for using a systems approach to minimize medication errors relating to product design and container closure design and thus enhance patient safety.

The recommendations in this guidance document are intended to provide best practices on how to improve the drug product and container closure design for all prescription and non-prescription drugs and biologic products regulated by the Center for Drug Evaluation and Research (CDER), which are referred to collectively in this guidance as products. The guidance also provides examples of product designs that have resulted in postmarketing medication errors…”

The document can be accessed here: FDA

Posted by Dr. Tim Sandle

THEORY AND PRACTICE FOR MEDICAL DIAGNOSIS

Details about a new book about medical pathology.

The IP Erasmus Project Classic and Modern Methods for Molecular Diagnostics in Human Pathology, coordinated by Transilvania University of Braşov between 2011-2013 had a follow up in the publication of a new volume. The book chapters were written or coordinated by the Project partners, as well as by other collaborators, interested both in the Project and in disseminating the results of their research.

Transilvania University of Bra ov

This book release contributes towards increasing the visibility of our university, strengthening its reputation in and outside Romania.

Posted by Dr. Tim Sandle

Proper Cleaning And Maintenance Of A Laboratory Balance

Keeping a balance cleaned and maintained can dramatically increase the life of your balance and the quality of your weighing results.

This is the subject of an article by Michelle Sheridan, Weighing Specialist, Sartorius Corporation, for Laboratory Network.

“Quality-relevant work steps, such as the measuring process itself, but also cleaning, calibration and maintenance, should be described in your Standard Operating Procedures (SOPs). Following your SOPs can mean that you will have consistent and precise weighing results at all times. Sartorius balances can meet your requirements for laboratory and production areas, and allow for easy and simple cleaning. Care of the balance’s cleanliness reduces disturbances during the weighing process.”

The article can be accessed here.

Posted by Dr. Tim Sandle

Alcohol Alters Gut Microbiome

Direct liver cell damage by alcohol has been well established as one of the primary causes of liver disease. Recent work by scientists at UC San Diego demonstrates that, in addition, alcohol can lead to liver disease by causing an imbalance in the gut microflora. Humans produce two natural broad-spectrum antimicrobial proteins called REG3B and REG3G that surveil gut mucosal bacteria and prevent overgrowth. Alcohol causes a down-regulation in the genes encoding for REG3B and REG3G leading to bacterial overgrowth, an increase in microbial translocation, immune activation and further cell damage, including the liver. Mice with REG3B/REG3G knockouts have more severe liver disease while mice with REG3G over-expression avoid liver damage. This work adds to the increasing importance of gut health on a wide range of disease.

For further details, see BDTI

Posted by Dr. Tim Sandle

MHRA data integrity guidance: 18 months on

Eighteen months have passed since the MHRA published its GMP data integrity guidance. Since then we have seen pharmaceutical industry make significant effort to implement the guidance globally. It has been encouraging to see industry stakeholders and regulatory partners adopting a common approach in their own publications and the messages and themes being echoed in online discussions, workshops and conference presentations.

David Churchwood has written an interesting post on the latest data integrity developments.

Here is an extract:

"During this busy period we have also been working on the next phase of MHRA guidance, which has a GxP focus (good laboratory practice, good clinical practice, good manufacturing practice, good distribution practice and good pharmacovigilence practice). Data integrity is important throughout the pharmaceutical lifecycle, and GxP regulatory requirements have a common focus of requiring confidence in the quality and the integrity of the data used for decision-making."

Here is a link to the new MHRA consultative document: MHRA data.



Posted by Dr. Tim Sandle

Crash Testing Bacteria (video)

Smashing into a solid wall at 670 miles per hour doesn’t even leave a mark. Brigham Young University Chemistry professor Daniel Austin and his graduate students are learning just how hard it can be to kill bacteria.

The research group, funded by NASA, is studying high velocity impact of bacterial spores. More specifically, the group is trying to find the speed limit above which bacteria won’t survive when they crash into a hard surface.

“There should be a velocity at which they’ll splat and die, but we haven’t reached it,” Austin says. “We can get pretty close to the speed of sound, and we’re planning to go to higher velocities in the near future, but it’s not easy to do.”

To test velocity, bacteria are loaded into a vacuum chamber and then launched by a blast of air at speeds nearing 300 meters per second.

The group’s recently published study in Planetary and Space Science is the first of its kind to test the impact survivability rate of bare bacteria.

Although the main focus of the research is answering the question of how much force the bacteria can withstand, NASA has funded the research because of the planetary protection implications of the study: if bacteria can survive the ejection from one planet and the impact of landing on another planet, there are potential concerns about cross contamination of bacteria between those planets. However, Austin is quick to acknowledge that there are other factors, like UV light, that may kill the bacteria in transition.

Even though the initial publication’s lead authors Brandon Barney and Sara Pratt have graduated, Austin continues to mentor current students as they develop the research. The group is now collaborating with Microbiology professor Richard Robison as they continue the quest for higher impact speeds. They anticipate that blasting bacteria at one kilometer per second (more than 2,200 miles per hour) should be more than enough to kill the bacteria, but the group hasn’t yet been able to create those speeds in the lab.

“We seem so frequently surprised at what bacteria can survive, and this just adds to the list,” Austin says. “Our understanding of the limits of life have expanded a lot since the 1970s as we find bacteria surviving and even thriving under extreme conditions.”

In testing the limits of bacteria, Austin’s team has additionally observed an unusual elasticity of the bacterial spores, which may have potential applications in nanotechnology.



Posted by Dr. Tim Sandle

Bacteria 'see' like tiny eyeballs

Biologists say they have solved the riddle of how a tiny bacterium senses light and moves towards it: the entire organism acts like an eyeball.

In a single-celled pond slime, they observed how incoming rays are bent by the bug's spherical surface and focused in a spot on the far side of the cell.

By shuffling along in the opposite direction to that bright spot, the microbe then moves towards the light.

Other scientists were surprised and impressed by this "elegant" discovery.

Despite being just three micrometres (0.003mm) in diameter, the bacteria in the study use the same physical principles as the eye of a camera or a human.

This makes them "probably the world's smallest and oldest example" of such a lens, the researchers write in the journal eLife.



Posted by Dr. Tim Sandle

Classifying the Unclassifiable

Some microbes are difficult to place within the current classification of living things. Didier Raoult believes we must break free of scientific convention or risk stifling new discoveries.

Didier’s column is hosted by the Translational Scientist. Here is an extract:

“About 20 years ago, I was investigating amoeba and the Legionella bacteria living within them, in a collection from Timothy Rowbotham. We identified five new species of Legionella and also made a surprising discovery – Gram-positive chlamydia-like bacteria living in amoeba. We tried and tried to amplify the newly discovered microbe, but all our attempts came to nothing, until eventually we started to question if it was a bacterium at all. We inspected the amoeba under an electronic microscope before and after extraction, and saw something that wasn’t bacteria-like at all, but instead looked very much like a virus. What we originally thought was a Legionella-like bacteria turned out to be mimivirus, a giant 0.4–0.8 µm virus with a 1.2 megabase genome.

Mimivirus is a very unusual virus. In fact, it’s debatable whether it is a virus at all.  It bears more resemblance to bacteria, archaea, and eukarya than to viruses. When we investigated mimivirus further, we found that the structural motif of its DNA and RNA polymerases are very old – we suspect that their origins may date back to before the operation of ribosomes. Mimiviruses can also be infected by viruses (virophages) themselves.”

For further details see: TS

Posted by Dr. Tim Sandle

Every Three Seconds Someone Will Be Killed by a Superbug

British government-commissioned report says drug companies must start investing in the creation of new antibiotic medicines or be fined, according to Reuters.

The new report says that if new antibiotics are not developed, someone will be killed by superbugs every three seconds by 2050.

It also predicted that by 2050, 10 million people will die every year just from antibiotic resistant infections, according to Reuters.

"The problem is that we are simply not developing enough new antibiotics and we are wasting the ones we have," reported Reuters.

Posted by Dr. Tim Sandle

E.coli O157

Public Health England (PHE) is investigating an outbreak of a strain of E. coli O157 which may be associated with eating leafy salad. To date 84 cases (figure correct as at 1 July 2016) of this strain of E. coli have been identified (77 in England, 5 in Wales, 1 in the Channel Islands and 1 in Scotland) with the majority of cases confirmed in the South West of England.

PHE has been working to establish the cause of the outbreak and identified that several of the affected individuals ate salad items prior to becoming unwell, although no individual supplier has been identified as the source. PHE is now reminding people to maintain good hygiene and food preparation practices in response to the current outbreak.

E.coli O157 infection can cause a range of symptoms, from mild diarrhoea to bloody diarrhoea with severe abdominal pain. On rare occasions, it can also cause more serious medical conditions and can be caught by eating infected food or by contact with infected animals. It can also be passed from an infected individual to another person if hand and toilet hygiene is poor.

Dr Isabel Oliver, director of PHE’s field epidemiology service, said:

“PHE has put in place heightened surveillance for this strain of E.coli and is and carefully monitoring the reporting of cases across the entire country. To assist with this investigation, we have convened a national outbreak control team to identify the source of infection and to ensure all necessary control measures are put in place.

“We continue to stress the importance of good hand and food hygiene practices at all times. It is vital to wash hands thoroughly using soap and water after using the toilet, before and after handling food and after contact with any animal and pets, including farm animals. Small children should also be supervised when washing their hands.

“We also urge people to remove any loose soil before storing vegetables and thoroughly wash all vegetables, fruit and salad items that will be eaten raw. These measures may reduce the risk of infection from any E.coli contaminated vegetables, fruit and salad but will not eliminate any risk of infection completely. PHE will work alongside the Food Standards Agency to provide any further necessary public health advice as investigations continue.”

The particular strain involved in the outbreak has been identified as phage type (PT) 34.

Posted by Dr. Tim Sandle

EMA Issues Statement on Brexit

The European Medicines Agency (EMA) has said the future location of the agency will be determined by common agreement between representatives of the Member States. This is as per a July 6, 2016 statement. Until this time, the EMA idnciates it will be conducting business as usual, and the outcome of the June 23 referendum will not affect the agency’s operations.

EMA says in the statement, “No Member State has ever decided to leave the EU, so there is no precedent for this situation. The implications for the seat and operations of EMA depend on the future relationship between the UK and the EU. This is unknown at present and therefore we will not engage in any speculations … We are confident that the Member States will take the most appropriate decision on EMA's location and arrangements in due course, taking also into account the complex political and legal environment generated by the outcome of the UK referendum.”

In the meantime, the EMA is working with various European Union institutions. The agency indicated it will update its stakeholders as soon as more information becomes available.

Source: EMA

Posted by Dr. Tim Sandle

European Pharmacopoeia 8th Edition: Supplement 8.8

A new supplement to the European Pharmacopeia has been issued. The points of interest are:

Revised texts - General Chapters

Chapter 2.2.3 Potentiometric determination of pH                                   

The main changes concern the choice of buffers used for the calibration of the pH meter which is now more flexible and does not start obligatorily with an initial calibration at pH 4.0. Furthermore, the chapter now allows the use of commercially available, certified reference materials as buffer solutions.

Chapter 2.2.46           Chromatographic separation techniques                           

Text modified to reflect current Ph. Eur. policy (system suitability, quantification).

Chapter 2.6.8 Pyrogens                                                                               

The text has been revised to include a reference to general chapter 2.6.30. Monocyte- activation test as a potential replacement of the test for pyrogens, therefore avoiding the use of live animals.

5.1.10  Guidelines for using the test for bacterial endotoxins              

This general chapter has undergone a general revision with the following scope.

A section has been added (section 2-4) to include aspects to be considered when establishing an endotoxin limit for a specific substance or product; also, the text has been revised to reflect the fact that an endotoxin limit is not always provided in a specific monograph.

Reference is made to general chapter 2.6.30. Monocyte-activation test as an alternative to the rabbit pyrogen test, and a recommendation is given to perform a risk assessment when using the bacterial endotoxin test as a pyrogenicity test, due to the potential for contamination by non-endotoxin pyrogens. In this respect, the previous section 11 concerning the replacement of the rabbit pyrogen test by a test for bacterial endotoxins has been substituted with a new text in agreement with a strategy to be applied for

testing of bacterial endotoxins or non-endotoxin pyrogens. A distinction is made between replacement methods already described in the Ph. Eur. and other alternative methods.

Reference is made to the use of alternative reagents to the Limulus amoebocyte lysate, such as recombinant factor C: this practice avoids the use of animal species.

A number of additional specific points have been included in the revision.

Method A is no longer declared as the reference method, and all methods A to F of general chapter 2.6.14. Bacterial endotoxins can be used. Where the method is stated in the monograph, the use of another method must be validated.

The expression ‘threshold endotoxin concentration’ has been replaced by the more appropriate expression ‘endotoxin limit concentration’ to harmonise with general chapter 2.6.30. Monocyte-activation test.

A new entry has been included in Table 5.1.10.-1 for formulations administered per square metre of body surface.

Chapter 5.3    Statistical analysis of results of biological assays and tests    

Equivalence testing: an explicit mention of ‘equivalence testing’ has been introduced in section 7.6.

Posted by Dr. Tim Sandle

Introducing Cleanrooms (book)

Want to know how cleanrooms work? Need to understand the recent ISO 14644 update? Have an interest in how physical design connects with contamination control? Then please see this new publication from Tim Sandle:

This book provides an introduction to cleanrooms and clean air devices in GMP environments. The book explains what cleanrooms are, the contamination risks, key design features, and the requirements for classifying and operating them. The book includes detail on the 2015 update to the international cleanroom standard ISO 14644 (Parts 1 and 2).

Length: 77 pages

Available as a printed book and as an e-book from Amazon.

FDA Drug Regulation Procedure

The Food and Drug Administration (FDA) has the highest responsibility of regulating the safety of drugs and other medicines sold in the U.S. The approval process is divided into a pre and post phase and drugs cannot be sold on the market without FDA approval.

By Michael Monheit

How Information About Drugs Is Collected By The FDA

The FDA collects facts regarding new drugs entering the U.S. market by following these basic guidelines:

Perform Tests

When a company seeks approval for selling a drug on the U.S. market, it must first perform a drug test on animals in a laboratory to establish how the drug works in humans. Once these tests are complete, the company must present an Investigational New Drug Application (IND) and must get FDA approval before it can test the drug on humans.

Clinical Trials

The company will then undertake a three-phased human clinical trial process, which is monitored closely by the FDA. This is undertaken to ensure that the drug is safe and effective for the general public.

Data Sent To FDA Regulatory Body For Review

Once the data has been collected from the clinical trials, the company sends this information from all the tests as a New Drug Application (NDA) to the Center for Drug Evaluation and Research (CDER) of the FDA. The CDER statisticians, pharmacologists, toxicologists and physicians study and review the information given by the company. If this review determines that the benefits are more valuable than the potential risks during use, the FDA approves the drug for selling on the market.

After-Market Performance And FDA Monitoring

After the drug hits the market, the FDA monitors its performance in a myriad of ways. Medwatch, the safety information, and reporting program generally receives reports about any side effects or adverse reactions to any drugs from health care practitioners, pharma companies, and consumers. Medwatch also accesses databases that gather information about health results and use of prescription drugs. This data enables FDA staff to understand and identify medicinal side effects.

If the drug presents unexpected risks, then consumers and healthcare practitioners are issued with Drug Safety Communication from the FDA. A new drug label is introduced with a safety concern statement to ensure that the drug is used in a safe and effective manner. For instance, Xarelto, a blood thinning medication was prescribed to millions of patients across the country to prevent stroke-causing blood clots. While there hasn't been a recall of the drug, the FDA has issued a series of safety communications about the drug, along with two black box warnings. BloodThinnerHelp.com has stated that this black box type of warning is the strictest form of warning that the FDA can issue for any drug. This warning comes because there is reasonable evidence of major side effects associated with Xarelto.

In some instances, drugs with major adverse effects will be withdrawn from being sold on the market because of the safety hazards they pose. This is because the FDA determines that the risks of that particular drug outweigh the benefits it provides. In December 2014, the FDA delivered an Adverse Reaction report about Xarelto resulting in low blood platelet counts or thrombocytopenia. Before this, the FDA issued several warnings about Xarelto to the public. The FDA cautions patients taking certain medications to discontinue the use of Xarelto, as a way to responsibly communicate with them.

Limitations Associated With Garnering Safety Data

While the FDA makes a strong effort to properly regulate drugs, some limitations are associated with safety data:

The FDA offers guidance during clinical trials, but the number of people is small in comparison to when the drug reaches the market. This makes it hard to determine side effects initially.
Even though experts review clinical trial data, it is hard to detect all possible side effects from the drug.
When people on other drugs take a certain drug, it is practically impossible to ascertain the kind of reactions the combination creates.

At the end, the FDA faces several challenges when evaluating new drugs. A particular drug will be effective for some people while it may produce side effects in others. Once a drug is on the market, the FDA must continuously review it during its lifecycle to ensure safety for patients.

Bio:

Michael Monheit, the managing attorney at Monheit Law, has been working to assist individuals and families who have been harmed by defective drugs and products. In fact, Mr. Monheit served on the Plaintiff’s Steering and Executive Committee for MDL 1148. He understands how stressful it can be to stand up to a major corporation and is committed to making sure that plaintiffs know they have someone on their side.

Bacterial Biomarker Hope

Necrotizing enterocolitis is one of the most common causes of death in premature infants – but by the time of onset, it’s already difficult to treat. Barbara Warner suggests that changes to the gut microbiome might allow pathologists to predict the disease.

Warner and her colleagues at the National Institute of Allergy and Infectious Diseases examined stool samples from 46 premature infants who developed NEC and 120 age-, birthweight- and birthdate-matched infants who did not. Genetic sequencing and statistical analysis revealed that the NEC population had significantly higher proportions of Gammaproteobacteria in their gut microbiome, and lower proportions of Clostridia and Negativicutes. This discovery raises many more questions for the researchers. “We hypothesize that the potential driver(s) behind this microbial signature could be related to the microbial community itself, the host, or both,” Warner explains. “Is it that specific pioneering microbes set the stage for subsequent colonization patterns? What then would be the determinants of those pioneering microbes? Alternatively, could it be that the host response is a determinant of which microbial community evolves? Preterm infants have an immature immune system, and it is increasingly evident that the gut microbiome and host immune systems are in a close reciprocal relationship that may be impacted by that immaturity.”

For further details, see The Pathologist

Posted by Dr. Tim Sandle