Monday 31 August 2020

Review of the causes of antimicrobial resistance

Antimicrobial agents particularly antibiotics have been critical in the fight against infectious diseases caused by pathogenic microorganisms including bacteria, fungi, viruses and protozoa (1). There usage in clinical medicine for treating infectious diseases has drastically leads to increase in the life expectancy of the human race over the past six decades. This is because the discovery and usage of antibiotics in infectious disease management has helped to reduce the rate of morbidity and mortality caused by infectious disease pathogens in human population. However, in recent years there has been a marked rise in the number and type of antimicrobial resistant organisms (2).

In relation to this subject, Tim Sandle has written an new article.

Here is the abstract:

Antibiotic resistance is one of the biggest challenges to the health sector worldwide, and this medical quagmire threatens our ability to effectively manage and treat some infectious diseases. Microbial resistance to antibiotics and/or antimicrobial agents has been documented not only against antibiotics of natural and semi-synthetic origin such as the penicillins, but also against some purely synthetic compounds (such as the fluoroquinolones) or those which do not even enter the cells (such as vancomycin). And unfortunately, the slow pace in the discovery and development of novel antibiotics have not actually kept pace with the emergence and rate at which bacteria develops and mount resistance to some available antibiotics (3).

Some infectious diseases including but not limited to tuberculosis, bacterial pneumonia, septicaemia, gonorrhoea, wound infections and otitis media are now becoming recalcitrant to treat with some available antibiotics because the causative agents of these diseases are fast becoming resistant to some available antibiotic therapy. These antibiotic resistant organisms have developed several novel ways and mechanisms that allow them to ward-off the antimicrobial onslaught of potent antimicrobial agents and/or antibiotics targeted towards them. This article reviews the primary resistance mechanisms.

The reference is:

Sandle, T.  (2020) Review of the causes of antimicrobial resistance, Microbioz India, 6 (3): 12-20

Access the article for free here:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Sunday 30 August 2020

Modern myth #6: Low endotoxin recovery affects all products

According to James Cooper, no one disputes that low recovery of lipopolysaccharide (LPS), as used for the LAL test control endotoxin, occurs in certain conditions, such as chelating buffers and detergents. However, this issue does not affect all products. 

Furthermore, the issue at hand is low lipopolysaccharide recovery rather than ‘low endotoxin’ recovery. Endotoxin is more sophisticated, being composed of a hydrophilic polysaccharide covalently linked to a highly conserved, hydrophobic lipid region. LPS and endotoxin do not behave in the same way (LPS activity varies due to the presence of various salts and detergents).

In addition, the use of a uniform screening test can reveal conditions of concern and legitimize the use of alternative naturally occurring endotoxin preparations for endotoxin challenge studies. However, to do required regulatory approval.


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Saturday 22 August 2020

New warning over ineffective hand sanitizers

Not all hand sanitisers are effective: How to spot a substandard or dangerous product. Many regulators have dropped some of the requirements for hand sanitisers in order to help to address supply problems. At the same time poor quality products have entered the market, including many containing toxic methanol. In this video, Tim Sandle explains what purchasers and members of the public need to watch out for:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Thursday 20 August 2020

Endotoxin Limits for Investigational Oncology Drugs and Biological Products

The U.S. FDA has issued an new guidance document titled “Setting Endotoxin Limits During Development of Investigational Oncology Drugs and Biological Products.” The document is currently in draft form (dated July 2020).

This guidance describes FDA’s recommendations to investigational new drug sponsors for setting endotoxin limits during the development of investigational drugs intended for use in combination with other approved drugs or for the codevelopment of two or more investigational drugs.

In keeping with the principles of facilitating drug development for serious and life-threatening diseases, this guidance outlines FDA’s current thinking on a risk-based approach to setting acceptance criteria for endotoxins during the clinical development of drugs intended to treat serious and life-threatening cancers.

For details see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Wednesday 19 August 2020

A Practical example of applying Quality Risk Management in GDP – Transportation Risks

This is about identifying and defining the risks. The MHRA write:

“Many companies present such summaries as a spreadsheet which assists communication, an essential part of QRM. The summary should be regularly re-evaluated and potential changes assessed during quality management review meetings. It is rare to find sound scientific justification for acceptance of a load subject to an excursion, and in the uncommon instances where a supplier or customer contacts the marketing authorization holder for stability information, it is often not directly comparable to the excursion experienced. Unfortunately, the most common reason for accepting a consignment with a temperature excursion is purely commercial, which may put patients at risk and undermines any risk management carried out by the company.

In some cases of quality risk management, attempts were made to inappropriately apply mean kinetic temperature to underestimate impact rather than develop good control and preventive measures.”

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Monday 17 August 2020

Minimizing microbial contamination on cleanroom surfaces

One design aspect is with the incorporation of antimicrobial materials into surfaces as a means to reduce microbial numbers (or at least to prevent microorganisms from growing). This addition has become commonplace in many hospitals1 and within food factories;2 however, the adoption has been slower within pharmaceuticals (where the use of antibacterial materials used to coat cleanroom surfaces is sometimes referred to as “biotrunking”). A second design aspect lies with the selection of surface properties of materials, so that surfaces can reduce the possibility of microbial attachment, making disassociated organisms easier to kill by disinfection. Combined, antimicrobial surfaces with specific topography has the potential to reduce microbial survival in cleanrooms.

In relation to this, Tim Sandle has written an article. The reference is:

Sandle, T. (2020) Minimizing microbial contamination on cleanroom surfaces, American Pharmaceutical Review, 23 (2): 30-35

In this article, different antimicrobial technologies together with physical properties are considered together with a review of available literature to examine the efficacy of such surface materials.

For details, see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Wednesday 12 August 2020

Mouthwashes could reduce the risk of coronavirus transmission

Sars-Cov-2 viruses can be inactivated using certain commercially available mouthwashes. This was demonstrated in cell culture experiments by virologists from Ruhr-Universität Bochum together with colleagues from Jena, Ulm, Duisburg-Essen, Nuremberg and Bremen. High viral loads can be detected in the oral cavity and throat of some Covid-19 patients. The use of mouthwashes that are effective against Sars-Cov-2 could thus help to reduce the viral load and possibly the risk of coronavirus transmission over the short term. This could be useful, for example, prior to dental treatments. However, mouth rinses are not suitable for treating Covid-19 infections or protecting yourself against catching the virus.

The results of the study are described by the team headed by Toni Meister, Professor Stephanie Pfänder and Professor Eike Steinmann from the Bochum-based Molecular and Medical Virology research group in the Journal of Infectious Diseases, published online on 29 July 2020. A review of laboratory results in clinical trials is pending.

Eight mouthwashes in a cell culture test

The researchers tested eight mouthwashes with different ingredients that are available in pharmacies or drugstores in Germany. They mixed each mouthwash with virus particles and an interfering substance, which was intended to recreate the effect of saliva in the mouth. The mixture was then shaken for 30 seconds to simulate the effect of gargling. They then used Vero E6 cells, which are particularly receptive to Sars-Cov-2, to determine the virus titer. In order to assess the efficacy of the mouthwashes, the researchers also treated the virus suspensions with cell culture medium instead of the mouthwash before adding them to the cell culture.

All of the tested preparations reduced the initial virus titer. Three mouthwashes reduced it to such an extent that no virus could be detected after an exposure time of 30 seconds. Whether this effect is confirmed in clinical practice and how long it lasts must be investigated in further studies.

The authors point out that mouthwashes are not suitable for treating Covid-19. "Gargling with a mouthwash cannot inhibit the production of viruses in the cells," explains Toni Meister, "but could reduce the viral load in the short term where the greatest potential for infection comes from, namely in the oral cavity and throat -- and this could be useful in certain situations, such as at the dentist or during the medical care of Covid-19 patients."

Clinical studies in progress

The Bochum group is examining the possibilities of a clinical study on the efficacy of mouthwashes on Sars-Cov-2 viruses, during which the scientists want to test whether the effect can also be detected in patients and how long it lasts. Similar studies are already underway in San Francisco; the Bochum team is in contact with the American researchers.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Tuesday 4 August 2020

The latest revision of EU GMP Annex 1 signals a new regulatory paradigm

A new edition of GMP Review has been published (edited by Tim Sandle). In the new edition is a paper by Dr. Sandle, looking at the essential elements of the latest revision of Annex 1 of EU GMP.
The aim of Annex 1 is to set out the minimum standards for the manufacture of sterile products (both aseptically filled and terminally sterilised), which takes place within cleanrooms and barrier devices. There is a major focus within the Annex on the need for a contamination control strategy, purposefully designed for each facility; and for each manufacturer to be using the principles of quality risk management.

While there are several essential points to consider for the contamination control strategy, those that appear to be given the greatest weighting (from this author’s reading of the text) are:
  • ·         Maintaining the critical processing zone.
  • ·         The aseptic assembly of filling equipment.
  • ·         Aseptic connections (these should be sterilized by steam-in-place whenever feasible).
  • ·         Special focus on aseptic compounding and mixing.
  • ·         The risks abound the replenishment of sterile product, containers and closures.
  • ·         Concerns around the removal and cooling of items from heat sterilizers.
  • ·         Staging and conveying of sterile primary packaging components.
  • ·         Aseptic filling, sealing, transfer of open or partially stoppered vials, including interventions.
  • ·         Loading and unloading of a lyophilizer.
It is unsurprising that each of these relate to aseptic processing, the highest-risk area of pharmaceutical manufacturing. 

The reference is:

Sandle, T. (2020) The latest revision of EU GMP Annex 1 signals a new regulatory paradigm, GMP Review, 19 (1): 4-6

For details, contact Tim Sandle.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

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