Wednesday, 31 July 2019

Big Investments for Human Microbiome Research

The Human Microbiome Project (HMP) was a U.S. National Institutes of Health (NIH) initiative that set the goal of identifying and characterizing the microorganisms which are found in association with both healthy and diseased humans, based on a budget of $115 million. The aim was to inform about human health or disease. Drawing on the wealth of data provided by the HMP, many companies are investing in microbiome based research.

Tim Sandle has written an article for BioPhrma Trends. Here is an extract:

"Capitalizing on new understanding of how imbalances in this ecosystem contribute to disease, a handful of startups aim to give physicians better weapons to fight conditions such as cancer, autoimmune disorders and infection. Examples include Vedanta Biosciences Inc, a start-up that has teamed up with New York University Langone Medical Center to study how bacteria can be used in the battle against tumors. Drug delivery is a related area with start-up Blue Turtle Bio utilizing bacteria from the gut microbiome as a drug delivery platform for supplemental enzymes intended to treat enzyme-deficient disease states."

To access, see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 30 July 2019

Australia - Standard for tablets, capsules and pills

News from the Australian TGA, new guidance for tablets, capsules and pills (Guidance for TGO 101).

This guidance is to help sponsors and manufacturers of medicines understand the role of the Therapeutic Goods Order No. 101 - Standard for tablets, capsules and pills (TGO 101, the Order) in ensuring that these types of therapeutic goods are of appropriate quality.

TGO 101 applies to three types of discrete oral dosage forms: tablets, capsules and pills. Assuring the quality of medicines manufactured in this way is important to ensure that they deliver their intended therapeutic effect and to provide a measure of continuing consistency in performance over time. Various categories of tablets are recognised dosage forms in Australian approved terminology for therapeutic goods. These include coated and uncoated tablets, effervescent tablets and modified release tablets. Compressed lozenges, which are designed to dissolve or disintegrate in the mouth, are considered to be tablets. Capsules can be hard or soft; the contents may be present as powders or liquids. Release of the active ingredients from capsules can also be modified in several ways, for example, enteric
capsules. Pills differ from tablets as they are manufactured using wet massing, piping and moulding. They can be coated, but usually contain only certain limited excipient ingredients and are typically manufactured and supplied as part of traditional medicine paradigms.


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 29 July 2019

Contamination control hot topics

There are a number of challenges facing pharmaceutical and biopharmaceutical companies in relation to controlling contamination in their facilities. To address some of these issues American Pharmaceutical Review recently hosted a contamination control roundtable.

Taking part were: Tony Cundell, Paula Peacos, Tim Sandle and Jeanne Moldenhauer.

Here is an extract from Tim Sandle:

“The problems will vary between different facilities, and these will center on the different sources of contamination in relation to people, air, water, transfer of items, equipment cleanliness, and bioburden of starting materials. The most difficult challenges are invariably around people: how personnel behave in cleanrooms, how they are gowned, and whether they follow the correct procedures. Although the regulations around personnel have largely remained unchanged, its noticeable that the number of warning letters and other regulatory citations have increased. The reason for this must rest with training, knowledge and with time (in terms of allowing operators sufficient time to carry out their duties and to clean and disinfect effectively).

“Keeping track of data is also a challenge. With large facilities in particular, assessing microbial and particulate trends remains important so that appropriate actions can be taken promptly. Furthermore, it is important to understand when the process is leaning out of control, to enable personnel to be alerted to a potential change in the process.”

The reference is:

Cundell, T., Peacos, P., Sandle, T. and Moldenhauer, J. (2019) Contamination Control Roundtable, American Pharmaceutical Review, 22 (3): 44-47

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 28 July 2019

Mechanism that prevents damage caused by shortened proteins

Human cells are made up of the following: a cell nucleus, which contains the genetic material in the form of DNA; and the cytoplasm, where proteins are built. In the cell nucleus, the DNA that contains the blueprint for the organism is rewritten into another form, messenger RNA, in order to transport the information so that these instructions can be used for protein production. Separated from the original transcript, the proteins can then be produced in the cytoplasm. The separation is important because the messenger RNA is not immediately usable; rather, a precursor (pre-messenger RNA) has to be produced that still contains areas that have to be removed before the messenger RNA reaches the cytoplasm. If these areas are not removed beforehand, then shortened or dysfunctional proteins are produced, which is dangerous for the cell.

The molecular machinery that cuts these areas out of the messenger RNA are the spliceosomes. They contain proteins and another type of transcripts of the DNA, the snRNA. The snRNA is not translated into proteins like messenger RNA, but together with the proteins, forms the molecular machinery: the spliceosome. In human cells, the snRNA of the spliceosomes also moves into the cytoplasm. In other organisms, such as baker's yeast, which is often used as a model organism in research, scientists had thought that the snRNA of the spliceosomes never left the cell nucleus. The reason for the evolutionary development to export snRNA before incorporation into the spliceosomes of human cells was also a mystery.


Daniel Becker, Anna Greta Hirsch, Lysann Bender, Thomas Lingner, Gabriela Salinas, Heike Krebber. Nuclear Pre-snRNA Export Is an Essential Quality Assurance Mechanism for Functional Spliceosomes. Cell Reports, 2019; 27 (11): 3199 DOI: 10.1016/j.celrep.2019.05.031

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 27 July 2019

EDQM inspections and trends of GMP deficiencies: Overview 2006 to 2018

A review of data from API inspections conducted by the EDQM between 2006 and 2018 is now available (PA/PH/CEP(18) 56 April 2019).

This document summarises the trends of deficiencies observed in EDQM inspections with reference to EU GMP and to the corresponding CEP dossiers.

This document is a review of data from API inspections conducted by the EDQM between 2006 and 2018. It covers: - the location of the inspections; - whether they were initial or re-inspections; - their outcome; - the distribution of the observed deficiencies to EU Good Manufacturing Practice (GMP) Part II area and criticality; - the frequency of the findings; - issues of data integrity.

For details, see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 26 July 2019

Purified water and water for injection standard update

The ISO standard for Purified water and water for injection has been update. This document specifies design, materials selection, construction and operation of Purified Water (PW) and Water for Injection (WFI) pretreatment and membrane-based production systems.

"ISO 22519:2019 - Purified water and water for injection pretreatment and production systems."

According to ISO, the document:
  • Allows users to specify water systems that fit specific needs without being experts in the water system field;
  • Allows users to decide whether the offered systems are safe, efficient and sustainable;
  • Enables national governments, state authorities and regulatory bodies to perform professional audits;
  • Provides auditors a standard check list to harmonize equipment and systems in the water industry;
  • Sets a high benchmark for suppliers of water systems all over the world, to be used as a point of reference for their systems and;
  • Will improve reliability of the water generation process methods and water product while reducing downtime needed for scheduled and non-scheduled maintenance.
Furthermore, as many different types of feed water are possible, different components and configurations are presented. The guidance provides a decision matrix is provided to give guidance for the different types of feed water.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 25 July 2019

How to Improve Worker Safety in the Pharmaceutical Industry

The pharmaceutical industry spends its days creating medications and equipment that save lives across the country and around the globe. The entire sector is subject to the highest quality control standards, but that focus on QC often leaves other areas — such as worker safety — lacking. How can managers and supervisors improve worker safety in the pharmaceutical industry?

Guest post by Megan Ray Nichols

Common Industry Problems

First, what are some common safety problems that workers in the pharmaceutical industry face?

First, there are physical hazards — cuts are among the most common injuries experienced in the industry, due to workers continually dealing with sharp instruments like scalpels and scissors. Broken glass can also contribute to the threat of physical injury, as well as problems with heat and electricity.

Chemical and biological hazards are also problematic for workers in this industry. The chemicals used to create drugs and treatments can be dangerous in large quantities, or if workers are exposed to them during the fabrication process. During recycling/reclamation, there is the threat of a biological hazard if a worker is injured by a used needle or scalpel during their workday.

Finally, there are psychological hazards that managers and supervisors will need to contend with. Workers in the pharmaceutical industry are often subjected to long hours and heavy workloads that can have a detrimental effect on their physical and mental health.

In 2017, there were more than 2.8 million non-fatal workplace injuries, with nearly 900,000 of these requiring the employees to stay home to recover.

With all of these concerns in mind, what can pharmaceutical companies do to ensure that their workers are safe throughout their workdays?

Finding a Solution

How can pharmaceutical supervisors and managers ensure that their workers are safe on the job?

The first step is to understand why employees take risks that result in workplace injuries. Employees may feel like safety isn't a priority or that they don't need to adhere to safety protocols because they've done their job without incident up until this point.

Once you understand why employees are taking risks, the next step is to work toward establishing a safety culture, one that covers all the potential risks and makes employees want to actively participate in workplace safety. Take the time to make safety everyone's job and everyone's priority. As part of this safety culture, offer continuing education programs that employees can take advantage of. Safety training shouldn't only take place during an employee's onboarding — it should be an endless process to reinforce those skills to create a safe workplace for everyone.

Additionally, safety software could help pick up the slack, so to speak, where a safety culture and continuing education fall short. Safety software includes a centralized information hub that all employees can access, as well as standards and compliance schedules that everyone will need to adhere to. Combining software with safety culture and continual training can help keep your pharmaceutical employees safe on the job.

The Future of Pharmaceutical Worker Safety

It's difficult to predict what the future of the pharmaceutical industry will look like. As technology and medicine both continue to advance, it's entirely possible that the sector will be completely unrecognizable by today's standards in a decade or two. One thing that will stand the test of time, however, is the need for worker safety. Start today by creating a safety culture, and investing in continued education for your staff.

Pharmaceutical workers are what keep the industry moving forward, from the hands that run the manufacturing equipment to the minds that create new drugs that will change lives. Make safety your priority, and work to make it everyone's responsibility, from the highest CEO to the newest laborer, and you will help to prevent on the job accidents.

Wednesday, 24 July 2019

How gut microbes eat our medication

In a new study, researchers at the University of California San Francisco, describe one of the first concrete examples of how the microbiome can interfere with a drug's intended path through the body. Focusing on levodopa (L-dopa), the primary treatment for Parkinson's disease, they identified which bacteria are responsible for degrading the drug and how to stop this microbial interference.

Parkinson's disease attacks nerve cells in the brain that produce dopamine, without which the body can suffer tremors, muscle rigidity, and problems with balance and coordination. L-dopa delivers dopamine to the brain to relieve symptoms. But only about 1 to 5% of the drug actually reaches the brain.

This number -- and the drug's efficacy -- varies widely from patient to patient. Since the introduction of L-dopa in the late 1960s, researchers have known that the body's enzymes (tools that perform necessary chemistry) can break down L-dopa in the gut, preventing the drug from reaching the brain. So, the pharmaceutical industry introduced a new drug, carbidopa, to block unwanted L-dopa metabolism. Taken together, the treatment seemed to work.

"Even so," lead researcher professor Maini Rekdal said, "there's a lot of metabolism that's unexplained, and it's very variable between people." That variance is a problem: Not only is the drug less effective for some patients, but when L-dopa is transformed into dopamine outside the brain, the compound can cause side effects, including severe gastrointestinal distress and cardiac arrhythmias. If less of the drug reaches the brain, patients are often given more to manage their symptoms, potentially exacerbating these side effects.

Maini Rekdal suspected microbes might be behind the L-dopa disappearance. Since previous research showed that antibiotics improve a patient's response to L-dopa, scientists speculated that bacteria might be to blame. Still, no one identified which bacterial species might be culpable or how and why they eat the drug.

So, the Balskus team launched an investigation. The unusual chemistry -- L-dopa to dopamine -- was their first clue.

Few bacterial enzymes can perform this conversion. But, a good number bind to tyrosine -- an amino acid similar to L-dopa. And one, from a food microbe often found in milk and pickles (Lactobacillus brevis), can accept both tyrosine and L-dopa.

Using the Human Microbiome Project as a reference, Maini Rekdal and his team hunted through bacterial DNA to identify which gut microbes had genes to encode a similar enzyme. Several fit their criteria; but only one strain, Enterococcus faecalis (E. faecalis), ate all the L-dopa, every time.

With this discovery, the team provided the first strong evidence connecting E. faecalis and the bacteria's enzyme (PLP-dependent tyrosine decarboxylase or TyrDC) to L-dopa metabolism.

And yet, a human enzyme can and does convert L-dopa to dopamine in the gut, the same reaction carbidopa is designed to stop. Then why, the team wondered, does the E. faecalis enzyme escape carbidopa's reach?

Even though the human and bacterial enzymes perform the exact same chemical reaction, the bacterial one looks just a little different. Maini Rekdal speculated that carbidopa may not be able to penetrate the microbial cells or the slight structural variance could prevent the drug from interacting with the bacterial enzyme. If true, other host-targeted treatments may be just as ineffective as carbidopa against similar microbial machinations.

"The molecule turns off this unwanted bacterial metabolism without killing the bacteria; it's just targeting a non-essential enzyme," Maini Rekdal said. This and similar compounds could provide a starting place for the development of new drugs to improve L-dopa therapy for Parkinson's patients.

The team might have stopped there. But instead, they pushed further to unravel a second step in the microbial metabolism of L-dopa. After E. faecalis converts the drug into dopamine, a second organism converts dopamine into another compound, meta-tyramine.

To find this second organism, Maini Rekdal left behind his mother dough's microbial masses to experiment with a fecal sample. He subjected its diverse microbial community to a Darwinian game, feeding dopamine to hordes of microbes to see which prospered.

Eggerthella lenta won. These bacteria consume dopamine, producing meta-tyramine as a by-product. This kind of reaction is challenging, even for chemists. "There's no way to do it on the bench top," Maini Rekdal said, "and previously no enzymes were known that did this exact reaction."

The meta-tyramine by-product may contribute to some of the noxious L-dopa side effects; more research needs to be done. But, apart from the implications for Parkinson's patients, E. lenta's novel chemistry raises more questions: Why would bacteria adapt to use dopamine, which is typically associated with the brain? What else can gut microbes do? And does this chemistry impact our health?

"All of this suggests that gut microbes may contribute to the dramatic variability that is observed in side effects and efficacy between different patients taking L-dopa," Balskus said.
But this microbial interference may not be limited to L-dopa and Parkinson's disease. Their study could shepherd additional work to discover exactly who is in our gut, what they can do, and how they can impact our health, for better or worse.


Vayu Maini Rekdal, Elizabeth N. Bess, Jordan E. Bisanz, Peter J. Turnbaugh, Emily P. Balskus. Discovery and inhibition of an interspecies gut bacterial pathway for Levodopa metabolism. Science, 2019; 364 (6445): eaau6323 DOI: 10.1126/science.aau6323

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 23 July 2019

Bispecific Antibody Development Programs - FDA

Image: Dr Josehp Ndieyira of UCL Medicine

The general regulatory and scientific considerations for bispecific antibodies, is a growing area of interest.
A new guidance document from the FDA, which refers to: “This guidance provides recommendations to assist industry and other parties involved in the development of bispecific antibodies. Discussion includes general considerations and recommendations for bispecific antibody development programs, as well as regulatory, quality, nonclinical, and clinical considerations in the context of bispecific antibody development programs. This guidance does not discuss development considerations for other multitarget therapies that are combinations of monoclonal antibodies or are antibody cocktails or polyclonal antibodies. Although this guidance is specific to bispecific antibodies, the principles discussed in this guidance may also be applicable to the development of other types of bispecific protein products.”

For details, see FDA -

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 22 July 2019

Why it’s time to focus on the cleanroom operator

The majority of contamination in a pharmaceutical facility, presuming that the air handling system is functioning as designed, that water systems are low in bioburden and are not leaking, and there is good control of in-coming materials, will derive from people. It follows that an effective contamination control strategy will focus on the control of operators. Control extends to behaviors, gowning and having the correct equipment, and this will be supported by periodic qualifications and underpinned by audits.
In relation to this, Tim Sandle has written a new article:

“This article addresses some of the key concerns relating to operators within cleanrooms, in the context of the risk operators pose in terms of microbial contamination. The article is divided into three sections. The first part looks at means to improve operator behaviors, the second part looks at how regular reviews by plant microbiologists or quality assurance staff can help to reinforce these behaviors, and the third part considers the idea of having ‘environmental control champions’ within the production facility.”

The reference is:

Sandle, T. (2019) Focusing on the Operator: Reducing Facility Environmental Contamination, American Pharmaceutical Review, 22 (3): 12-17

For further details, contact Tim Sandle

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 21 July 2019

EMA facilitates engagement with medicine developers to combat antimicrobial resistance

The European Medicines Agency (EMA) is opening up the early dialogue available through its Innovation Task Force (ITF) to all medicine developers who work on therapeutic approaches for the treatment or prevention of bacterial and fungal infections. ITF is a forum for dialogue between regulators and developers of innovative emerging therapies, methods and technologies, in the early stages of research and development. ITF is usually reserved for innovative medicines. Given the growing threat to public health caused by antimicrobial resistance and the need for new treatments, EMA is inviting all developers working on medicines for the treatment or prevention of life-threatening microbial infections to enter into early dialogue with the Agency to help strengthen the drug development pipeline for new antimicrobials.

The emerging and steady increase of microbes that are resistant to antimicrobial treatments threatens the effective treatment of patients with infectious diseases. According to a WHO report, approximately 700,000 people die from drug resistant infections globally each year, a figure that could rise to 10 million deaths globally per year by 2050 under the most alarming scenario if no action is taken. Without a sustained effort to contain antimicrobial resistance, common diseases are becoming untreatable and lifesaving medical procedures riskier to perform.

The ITF will facilitate an early interaction and broad-ranging discussions between innovators and regulatory authorities, which will help developers’ orientation and subsequent use of formal regulatory tools such as EMA’s scientific advice. The service is free of charge and any new medicinal product for the treatment of a life-threatening or debilitating fungal or bacterial infection would be considered for discussion in the ITF.

This platform for early dialogue will ultimately contribute to prioritising and speeding up the development of antimicrobial medicines, which is in line with the European Parliament Resolution of 13 September 2018 on "A European One Health Action Plan against Antimicrobial Resistance".

Interested medicine developers are encouraged to complete the ITF briefing meeting request form and send it to to discuss their development plans for medicinal products addressing bacterial and fungal infections.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 20 July 2019

Salmonella resistant to antibiotics of last resort

Researchers from North Carolina State University have found a gene that gives Salmonella resistance to antibiotics of last resort in a sample taken from a human patient in the U.S. The find is the first evidence that the gene mcr-3.1 has made its way into the U.S. from Asia.
There are more than 2,500 known serotypes of Salmonella.

In the U.S., Salmonella enterica 4,[5],12:i:- ST34 is responsible for a significant percentage of human illnesses. The drug resistance gene in question -- known as mcr-3.1 -- gives Salmonella resistance to colistin, the drug of last resort for treating infections caused by multidrug-resistant Salmonella.

"Public health officials have known about this gene for some time," says Siddhartha Thakur, professor and director of global health at NC State and corresponding author of the research. "In 2015, they saw that mcr-3.1 had moved from a chromosome to a plasmid in China, which paves the way for the gene to be transmitted between organisms. For example, E. coli and Salmonella are in the same family, so once the gene is on a plasmid, that plasmid could move between the bacteria and they could transmit this gene to each other. Once mcr-3.1 jumped to the plasmid, it spread to 30 different countries, although not -- as far as we knew -- to the U.S."

Thakur's lab is one of several nationally participating in epidemiological surveillance for resistant strains of Salmonella. The lab generates whole genome sequences from Salmonella samples every year as part of routine monitoring for the presence of antimicrobial-resistant bacteria. When veterinary medicine student Valerie Nelson and Ph.D. student Daniel Monte did genome sequencing on 100 clinical human stool samples taken from the southeastern U.S. between 2014 and 2016, they discovered that one sample contained the resistant mcr-3.1 gene. The sample came from a person who had traveled to China two weeks prior to becoming ill with a Salmonella infection.


Daniel F. Monte, Valerie Nelson, Louise Cerdeira, Shivaramu Keelara, Shermalyn Greene, Denise Griffin, Shadia Rath, Robbie Hall, Nichole Page, Paula J. Fedorka-Cray, Siddhartha Thakur. Multidrug- and colistin-resistant Salmonella enterica 4,[5],12:i:- sequence type 34 carrying the mcr-3.1 gene on the IncHI2 plasmid recovered from a human. Journal of Medical Microbiology, 2019; DOI: 10.1099/jmm.0.001012 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 19 July 2019

Ebola Outbreak - Global health Emergency

ASTMH (American Society of Tropical Medicine and Hygiene) welcomes the WHO’s declaration of the Ebola outbreak in the Democratic Republic of the Congo as a global public health emergency. The declaration will help to mobilize the additional support necessary for the men, women and children who are suffering from this disastrous and devastating disease, and for the brave health workers and researchers striving tirelessly to stop it.

This new case in Goma is one more of the many warnings of the powder-keg nature of this Ebola outbreak. The West African Ebola outbreak in 2014 was a demonstration of how interconnected we all are. Every country must pay attention to this fragile situation and do more to find solutions to this public health crisis. With new vaccines and the scientific tools available, the WHO’s declaration is a significant step in the right direction.

“While the progress we’ve seen in developing new drugs and vaccines against Ebola is remarkable, we need to make further biological breakthroughs and match them with a political breakthrough,” said ASTMH President Chandy C. John, MD, MS, FASTMH. “ASTMH is eager to work with decision-makers and government leaders in a worldwide collaborative effort to end this outbreak and prevent future outbreaks. As tropical infectious disease experts, we know what is at stake here. We believe it is past time to work together to bring this terrible outbreak to an end.”

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 18 July 2019

The Battle to Control HAIs

Floors, often overlooked in the past as a major factor of environmental contamination leading to increased HAI rates, are, in fact, a contributor to this very expensive and life-impacting problem. Studies have shown that floors harbor HAI pathogen organisms. These pathogens may not be neutralized by using mops that bind disinfectants or may be transported through unexpected means, including socks or laundered mops damaged by the laundering process and reducing their ability to effectively clean or disinfect the floor.

New from Infection Control Today:

  • Download this whitepaper, which discusses:

  • Human and financial implications of HAIs.
  • Microfiber laundered mops retain residual pathogens.
  • Impact of laundry processes on microfiber’s structure and efficacy.
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Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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