Monday, 25 March 2019

Biocontamination control for pharmaceuticals and healthcare

A new book has been published – “Biocontamination Control for Pharmaceuticals and Healthcare” by written Tim Sandle.

The book outlines a biocontamination strategy that tracks bio-burden control and reduction at each transition in classified areas of a facility. This key part of controlling risk escalation can lead to the contamination of medicinal products, hence necessary tracking precautions are essential. Regulatory authorities have challenged pharmaceutical companies, healthcare providers, and those in manufacturing practice to adopt a holistic approach to contamination control. New technologies are needed to introduce barriers between personnel and the environment, and to provide a rapid and more accurate assessment of risk. This book offers guidance on building a complete biocontamination strategy.

Key features of the book are:

Providing the information necessary for a facility to build a complete biocontamination strategy.
Helping facilities understand the main biocontamination risks to medicinal products.
Assisting the reader in navigating regulatory requirements.
Providing insight into developing an environmental monitoring program.
Covering the types of rapid microbiological monitoring methods now available, as well as current legislation.

Table of Contents

1 Introduction
2. Sources of microbial contamination and risk profiling
3. GMP, regulations and standards
4. Biocontamination control
5. Introduction to cleanrooms and environmental monitoring
6. Viable monitoring methods
7. Selection of culture media
8. Non-viable monitoring
9. Rapid microbiological methods
10. Designing an environmental monitoring programme
11. Special Types of Environmental Monitoring
12. Cleanrooms and microflora
13. Assessment of pharmaceutical water systems
14. Data handling and trend analysis
15. Bioburden and endotoxin assessment of pharmaceutical processing
16. Risk assessment and investigation for environmental monitoring
17. Assessing and removing contamination risks from the process
18. The human factor
19. Biocontamination deviation management

374 pages


Sandle, T. (2019) Biocontamination Control for Pharmaceuticals and Healthcare, Academic Press, London, UK

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 24 March 2019

ICH Q12 revision process

The EMA has published industry comments gathered during its public consultation for the ICH draft guideline on pharmaceutical product lifecycle management (ICH Q12).
This new guideline is proposed to provide guidance on a framework to facilitate the management of post-approval chemistry, manufacturing and controls (CMC) changes in a more predictable and efficient manner across the product lifecycle. This guideline aims to promote innovation and continual improvement, and strengthen quality assurance and reliable supply of product, including proactive planning of supply chain adjustments. The guideline strives to promote, for regulators (assessors and inspectors), an improved understanding of the Applicants' pharmaceutical quality systems (PQSs) for management of post-approval CMC changes. This new guideline is intended to complement the existing ICH Q8 to Q11 guidelines.

For details, see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 23 March 2019

Antimicrobial Coating "Liquid Guard" Nominated

Getting sick whether at home, in school, or perhaps worse of all at a medical centre is often the results poor hygiene and microbes being passed from surfaces touched. Despite some attempts, no products have done well at solving this problem. Nano-Care Deutschland AG, a spin-off of Leibniz Institute of New Materials Saarbrücken (INM), seems to have answered the riddle correctly, with their recently launched new product – Liquid Guard, a “wipe on” invisible coating with permanent antimicrobial effects, recently winning a nomination for the very well-respected German Innovation award 2019.

“We worked hard to develop a product that was not just excellent for protecting against microbes in hospitals and medical centers, but also at home and in the office,” commented Oliver Sonntag, CEO of Nano-Care AG. “Don't forget everything we touch is a potential carrier of sickness, so protecting ourselves is a must when it comes to toilet seat cover, door handles, and so on. We quite are quite pleased the well-regarded German Innovation Awards 2019 saw has seen how useful and effective our product is.”

Liquid Guard acts as a powerful shield against nearly every germ a person could think of (including MRSA the bane of hospitals and medical centres), while also defending from mold, fungi, yeast and other forms of odor and sickness-causing bacteria. The “wipe on product” is clear and each coating can last from several months to a year.

Anyone can use Liquid Guard easily, by just applying it and wiping. The German Innovation Award is a new innovation prize that awards projects and products that have an impact, by dint of the added value, or new solutions they deliver. The award is held annually.

To learn more, visit:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 22 March 2019

Antimicrobial resistance: interventions to reduce antibiotics

Fears around leaving infectious diseases untreated and poorly enforced antibiotic supply controls could hamper efforts to reduce the use of antibiotics in low to middle income countries, according to a new study from the University of Warwick.

Published in the journal Trials and led by Dr Marco J Haenssgen, Assistant Professor in Global Sustainable Development, the study demonstrates that contextual factors, such as local health policies, influence the results of clinical trials of medical interventions. The landmark study is one of the most detailed qualitative analyses of the context of clinical trials in antimicrobial resistance ever conducted. It calls for the routine collection of social data alongside clinical trials to help tailor the local appropriateness of clinical interventions and help researchers interpret their findings.

By better recording these contextual influences, the researchers argue that interdisciplinary research collaborations between the social and medical sciences can help tackle global challenges such as drug resistance more effectively.

The study analyses clinical trials in Myanmar, Thailand, and Vietnam with a total of 4,446 participants, that aimed to test the effectiveness of a five-minute finger-prick blood test to reduce antibiotic prescriptions for fever patients in primary healthcare. The test measured C-reactive protein levels in the participants’ blood, helping healthcare workers such as nurses and doctors to decide whether the cause of the febrile illness was likely to be bacterial, in which case an antibiotic could be prescribed.

The research by Dr Haenssgen’s team complemented these trials and identified differences in adherence to the results of the test in patients and clinicians, both across and within the sites - in some clinics, physicians prescribed antibiotics despite a negative test result in as much as 71% of cases. They then determined the reasons for the disparities through the analysis of nearly one million words of qualitative material from 130 interview and group discussion participants across the three countries.

They found that if antibiotics were over-abundant or if healthcare workers were worried about deadly infectious diseases they were less likely to follow the guidance provided by the biomarker test. Similarly, if long and dangerous journeys prevented patients from follow-up visits to primary health centres or if they struggled to understand the purpose of the test, then patients may be more likely to ignore the results and buy antibiotics without prescriptions from local grocery stores and pharmacies – making the intervention seemingly less effective.

The study further argues that such clinical trials could also exclude different parts of the relevant target population, as some people struggle with accessing healthcare and others might not consume antibiotics for fevers but, for instance, open wounds and other conditions for which the biomarker test is not currently being used.

Diagnostic biomarker tests are one of the main strategies to tackle drug resistant infections, which the World Health Organization named one of the “ten threats to global health in 2019.” As the World Bank d=kOzPryvBvyrPOU7HpAx0wLVvbLl3gk5AokmRjylDs6wqxs6xI8jm_vxpUnzOf0Twocls845zNyyQ0DW8nhSDA9lnihQSVQI362Wz4SMBNqXjg4UsSA3qHN1AQVBf6IXWag4Q2Orr2oBVs21TItxD2fBoFKgsU5EejTNojefxem9xYOJ9AbibmBgVqL0O0e9RNw2">warns
that drug resistance could push 24 million people into poverty by 2030 and threatens the achievement of the Sustainable Development Goals, Nesta (a charity) is running the Longitude Prize challenge of £10m for the development of effective diagnostic solutions to help end the crisis.

Lead author Dr Marco Haenssgen said: “An example of how context affected clinical adherence relates to the strong antibiotic policies and the ways to manage patients without antibiotics in Thailand. Some doctors had a surprising oversupply of antibiotics to the extent that they almost felt they needed to prescribe to get rid of the surplus medicine. This was of course not the only way in which clinician adherence varied, but it shows how the same AMR intervention might or might not work, and how we need to tailor our interventions specifically for each country – one size doesn’t fit all contexts!

“For researchers, more contextual data from clinical trials means that we will be able to carry out meta-analyses to identify which contextual factor (e.g. poverty, complementary health policy) matters for the successful operation of a new intervention. That would then inform a design toolkit for clinicians that can guide them in identifying appropriate interventions, or advocating for changes in policy.

“The opportunity that presented itself to us in this research is rare – social-medical research across three low- and middle-income countries does not just require a lot of coordination and patience, but also an open-minded research team. We were fortunate to have all in place, which enabled us to inform the tools and techniques being used to fight the superbug crisis, and to advance interdisciplinary research methodologies more broadly. This wasn’t easy, but when we consider the emerging challenges to planetary health and sustainable development, interdisciplinary collaboration is the way to go.”

The social science research was led by Asst Prof Marco J Haenssgen (Global Sustainable Development at University of Warwick) in collaboration with Ms Nutcha (Ern) Charoenboon (Research Officer for the Antibiotics and Activity Spaces Project), Ms Yuzana Khine Zaw (Research Intern for the Antibiotics and Activity Spaces Project and PhD Student at the London School of Hygiene and Tropical Medicine), and Dr Nga TT Do (Researcher at the Oxford University Clinical Research Unit, Hanoi). The clinical trials were led by Prof Heiman FL Wertheim (Radboud University Medical Centre) and Prof Yoel Lubell (University of Oxford) and implemented by Dr Thomas Althaus (Mahidol-Oxford Tropical Medicine Research Unit, Bangkok) and Dr Nga TT Do. The study was funded by the Wellcome Trust (ref. 105605/Z/14/Z and 105032/Z/14/Z), the Wellcome Trust Major Overseas Programme, the Center for Disease Dynamics, Economics and Policy (CDDEP), and the Economic and Social Research Council (ref. ES/P00511X/1).

Haenssgen, M. J., Charoenboon, N., Do, N. T. T., Althaus, T., Khine Zaw, Y., Wertheim, H. F. L., et al. (2019). How context can impact clinical trials: a multi-country qualitative case study comparison of diagnostic biomarker test interventions. Trials. DOI: 10.1186/s13063-019-3215-9

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 21 March 2019

FDA report: Investigation of the California-linked romaine lettuce outbreak of E. coli O157:H7 in November 2018

The FDA reported the results of California-linked romaine lettuce outbreak of E. coli that caused the removal of products from shelves just before Thanksgiving. The CDC found one match to the outbreak strain of E. coli O157:H7 in the sediment of an on-farm water reservoir, used for irrigation by Adam Bros. Farming, Inc., in Santa Barbara County. The strain was not detected in any other samples collected during this investigation.

On December 17, 2018, the farm issued a recall of romaine lettuce and other products (red leaf lettuce, green leaf lettuce and cauliflower) that could be contaminated due to use of water from the same reservoir. Currently, the FDA believes that the use of water from the reservoir was the source of the lettuce contamination, since the outbreak strain of E. coli O157:H7 was found in sediment from the reservoir and in no other sampled locations. This does not explain how lettuce grown on other farms got contaminated.. .… Read More

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 20 March 2019

SkinBioTherapeutics on track for development of scientifically based skin microbiome treatments

UK based SkinBioTherapeutics is developing a range of scientifically validated treatments derived from probiotic bacteria for use in cosmetics, infection control products and for the treatment of eczema.

Led by Professor Cath O’Neill from Manchester University, a world leader in this field, the company will have the results of a double blinded, cream efficacy study in 120 volunteers in a few weeks which will be shared with interested commercial partners. This follows successful clinical studies in ensuring that the treatments do not irritate and that that they are effective moisturisers.

The skin, the body’s largest organ, is colonised by a diverse range of microorganisms which has to be managed for long term good health. SkinBioTherapeutics, patented technology, has developed a range of products based on lysates - extracts of probiotic bacteria - which will help keep the skin healthier and treat certain conditions.

The lysates work by increasing the skins barrier integrity through enhancing the formation of multi-protein complexes called 'tight junctions'. Tight junctions seal the space between adjacent cells to prevent the passage of toxins, molecules and ions through these spaces. They also help to protect the skin from infection by outcompeting harmful pathogens and increase the rate of skin healing in response to injury.

CEO Professor Cath O’Neill commented “My colleague Professor Andrew McBain and myself have been working on understanding the skin microbiome for some years. We believe that there are many treatments which could develop from our research and it has been very rewarding to have such interest from both leading commercial concerns and academia. What we believe is very important is that microbiome treatments are based on science and rigorous human studies.”

The company has also made significant progress both in the scale up of its manufacturing processes and the development of a medical device dossier for the eczema programme for submission to the regulatory authorities.

A fuller account of SkinBioTherapeutics activities is available at

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 19 March 2019

Gamma irradiation cleans up

Disposable medical devices, including syringes, implants, cannulas (flexible tubes) and intravenous sets, are required to be sterile. Given that plastics cannot be subjected to sterilisation by heat, for plastic medical devices, the primary way in which they are sterilised is by gamma irradiation (electromagnetic irradiation).

Article by Tim Sandle.

There are alternative sterilisation processes for medical devices, including electron beam irradiation, ion beams and ethylene oxide gas, but the advantage of using gamma irradiation
is that it has a high penetration capability. This means that products that are relatively dense or moderately sealed can be sterilised in a fairly straightforward way. However, although gamma irradiation is an established process, various factors need to be weighed up.

"Gamma irradiation sterilises materials through the energy from photons of gamma radiation."

These include microorganisms that are typically on the device during manufacture (this natural load can be reduced substantially when devices are assembled in cleanrooms), the type of polymer used to manufacture the device, and the selection of appropriate process controls.

Irradiation is the process by which an object is exposed to radiation. Gamma irradiation sterilises materials through the energy from photons of gamma radiation (provided by a radioisotope) being transferred to the electrons in the target material. This creates highly active electrons (a process called ionisation) and highly active free radicals. These physical elements are capable of breaking the DNA within microorganisms and spores, which destroys them as well as prevents them from replicating, thus causing sterilisation.


The source of gamma irradiation used at most facilities is a radioisotope called Cobalt-60, which is specially manufactured for use by irradiation plants. Cobalt-60, which performs as an energy source, is normally derived as pellets and placed into stainless steel tubes known as pencils. The pencils are, in turn, housed in a reinforced concrete structure called a cell (usually two metres thick) because shielding from gamma rays requires large amounts of mass.

The Cobalt-60 pencils within the cell are held in a source rack, which has two operating positions. These are the storage position where the rack is either immersed in water or sometimes deep within concrete, and the operational position whereby the rack is raised. It is when in the operational position that sterilisation takes place. The storage position is needed because Cobalt-60 cannot be turned off; it continues to emit radiation.

"The source of gamma irradiation used at most facilities is a radioisotope called Cobalt-60."

Sterilisation by gamma radiation is a cold process and does not require any special physical changes like heat or pressure in order to activate the sterilisation process. The process involves the product being placed into special containers called totes, usually constructed from aluminium. The amount of product that can go into a tote is established during validation. On this basis, it is important to check the dimensions and weight of the product to be sterilised prior to beginning the process.

For the sterilisation process, the Cobalt-60 source is raised and the tote containing products is moved around the source. The movement is at various heights and involves the rotation of the tote so that different sides of it are exposed. This ensures that adequate penetration by the radiation occurs and that the required dose of the product is achieved. The speed at which this takes place depends upon the dose required. The dose is established during the validation. Because Cobalt-60 has a relatively short half-life (less than five-and-a-half years) the rate of decay varies and the process speed needs to be checked each day to ensure that the product in each cycle receives the correct dose.
Proving sterilisation

Sterilisation is demonstrated using devices called dosimeters, which measure the theoretical radiation dose received by the product. Dosimeters are plastic devices which contain a complex dye. After exposure to gamma irradiation the dye inside the dosimeters alters and the greater the level of irradiation, the darker the dye becomes.

"Sterilisation is demonstrated using devices called dosimeters, which measure the theoretical radiation dose received by the product."

Dosimeters are placed in the tote and on the packaging of the product. At the end of the sterilisation cycle, the dose is checked by testing the dosimeters. This is undertaken by measuring their optical density using a spectrophotometer and the material thickness with a microscope. The relationship between these two variables allows the dose calculation to be made.

To provide a visual confirmation of sterilisation, it is common to use chemical indicator labels on the outer packaging of the medical devices. When sterilisation is complete, the indicator labels change colour (often from yellow to red). While such labels provide a rapid way of assessing effective sterilisation they are not a substitute for using and testing dosimeters.
The importance of validation

Before any sterilisation process can be carried out on a medical device it requires validating. This is in order to establish process parameters that can be replicated for routine sterilisation and to show that the sterilisation cycles can achieve a sterility assurance level of 1×10-6. This is a theoretical concept where it is assumed that, in terms of probability, no more than one item sterilised out of one million would contain one or more microorganisms after the completion of the sterilisation process.

Validation involves determining the dose required to be absorbed by the product in order to sterilise it. This is called the dose profile and it is assessed by dose mapping. For medical devices the validation is typically performed in triplicate. The unit of absorbed dose is the Gray (Gy), typically measured as kiloGrays (kGy).

"Because most medical devices are constructed from plastic, there are inherent degradation risks in any sterilisation process."

The Gy is defined as the absorption of one joule of ionising radiation by 1kg of matter. The dose required by medical devices varies and a careful balance needs to be struck between having a sufficient dose in order to ensure sterilisation happens but not too great a dose that the material is damaged (such as becoming brittle or discoloured) or that a chemical reaction takes place which cause a chemical substance to leach out of the material.

Because most medical devices are constructed from plastic, there are inherent degradation risks in any sterilisation process. Degradation is the change in properties of a polymer, such as tensile strength, colour, shape or molecular weight. For critical items long-term stability studies are often undertaken to study the material over its shelf-life and across the typical storage temperatures. This involves physicochemical testing. A common radiation dose used for plastics is in the range 15-25kGy, although it can be higher for denser materials.

The dose profile is based on assessing the absorbed dose. This is based on the density of the medical device, the pack size, the amount of wrapping around the product, the dose rate and the exposure time. This will vary between sterilisation plants because each plant design will be different. This means that validation is not transferrable between plants and must be repeated if a different sterilisation plant is selected.

High standards

It is important that sterilisation facilities operate to standards. The most common standard adopted for gamma irradiation is ISO 11137-1:2006, developed in association with the Association for the Advancement of Medical Instrumentation.

"The most common standard adopted for gamma irradiation is ISO 11137-1:2006."

Standards are important so that the manufacturers of medical devices know that the process is being undertaken to a recognisable guideline and that there is a level of consistency between different sterilisation plants. The adoption of a standard also provides the medical device manufacturer with a template with which to construct an audit of the sterilisation plant.

Gamma irradiation has distinct advantages and is one of the most effective sterilisation methods available if the validation is sufficiently robust. If it is not, however, then the sterilisation either simply will not work or the medical device itself will be at risk from material degradation.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 18 March 2019

Kenneth G. Chapman Award

Tim Sandle, Ph.D., Head of Microbiology and Sterility Assurance, Bio Products Laboratory Limited, has been awarded the prestigious Kenneth G. Chapman Award by the Institute of Validation Technology.

Ken Chapman served with Pfizer Inc for 43 years in various Production, R&D, and QC roles, retiring as Director of Corporate Quality Assurance Audit in 1994. He served on the Editorial Review Board of Pharmaceutical Technology and, in October 1988, was presented the Pharm. Tech. Publisher's Award at E. Rutherford, NJ. He also served on the Editorial Advisory Board of the Journal of Validation Technology and was honored with the Life Time Achievement Award by the Institute of Validation Technology (IVT).

See IVT -

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 17 March 2019

New bacteria discovered in human blood

Two new species of bacteria have been found in the blood of patients in China.

News from the Microbiology Society:

The bacteria were found in the blood of two human patients during blood tests as part of routine medical care. The new bacteria, both of which are in the Enterobacter genus, were found to be resistant to multiple antibiotics.

Enterobacter are not usually harmful and exist as part of the healthy gut microflora. However, when these bacteria enter the bloodstream, respiratory system or the urinary tract they can cause disease. Enterobacter infection in the blood can lead to diseases including meningitis and bacteraemia, and Enterobacter in the lungs can lead to pneumonia. Bacteraemia is the presence of bacteria in the bloodstream and can lead to serious conditions including sepsis and septic shock.

The researchers named the newly discovered species Enterobacter huaxiensis and Enterobacter chuandaensis.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 16 March 2019

Water microbiota fact sheets

Pharmig has launched the latest in the on-going series of microorganism fact sheets. The factsheets provide descriptive information and characteristics of the main organisms, to help microbiologists tasked with investigations, together with full colour colony and growth characteristics, and typical Gram-stain profiles, to assist those who carry out identifications.

The latest series looks at the types of microbes associated with pharmaceutical grade water, including Pseudomonas aeruginosa and Stenotrophomonas maltophilia. The fact-sheets are written by Dr. Tim Sandle.

These laminated sheets are ideal for use on the laboratory bench, to assist microbiologists as they carry out their work, and as handy training aids.

To find out more, see the Pharmig publications page here:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 15 March 2019

Genes that Help Harmful Bacteria Thwart Treatment

A Rutgers-led team has discovered two genes that make some strains of harmful Staphyloccocus bacteria resistant to treatment by copper, a potent and frequently used antibacterial agent.

The discovery shows that Staphyloccocus aureus can acquire additional genes that promote infections and antibacterial resistance and may open new paths for the development of antibacterial drugs,
according to a study in the Journal of Biological Chemistry.

Researchers at Rutgers University–New Brunswick found the two genes in some strains of S. aureus bacteria. The genes protect the germs from copper, which is increasingly used in the global fight against severe infections.

The Staphylococcus aureus bacterium – a leading cause of serious and life-threatening infections in the United States – is highly resistant to antibiotics. Some strains of S. aureus have newly acquired genes embedded in their genome in pieces of DNA called transposons. DNA can be transferred from one organism to another, and transposons help the acquired DNA rapidly become a permanent part of the recipient’s chromosome.

Transposons aid in the spread of genes that can give rise to bacteria that are resistant to antibiotics and more likely to cause disease. The newly discovered genes are encoded within a transposon.

This process likely contributed to the recent North American epidemic of staph infections, according
to Jeffrey M. Boyd, study senior author and associate professor in the Department of Biochemistry and Microbiology in Rutgers’ School of Environmental and Biological Sciences.

Here’s the full story with an image:

Here’s a link to the study:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 14 March 2019

Clean facilities round-table

Tim Sandle was a participant in the American Pharmaceutical Review Clean Facilities Roundtable, December 2918, with Tony Cundell, Claire Briglia, Paula Peacos, David Jones, Tim Sandle, Poonam Bhende, and Donald Singer.

Here is an excerpt, from Tim Sandle: “Rapid methods will become more important, in order to address the problem with conventional microbiology of reacting several days later to an event. One more recent development with environmental monitoring methodologies is with optical instruments which aim for the real-time counting of microorganisms and non-viable particles from samples of air. Optical spectroscopy is an analytical tool that measures the interactions between light and the material being studied. These instruments work by elastic light scattering.”

For the full feature, see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 13 March 2019

Review of Standards for Disinfectants; and associated guidance

The Australian TGA have initiated a review into hard surface disinfectants. The TGA
invites comments on their proposed update. It is intended that the updated TGO will incorporate all relevant regulatory requirements, comprising:

Updated sections of TGO 54 that clarify existing requirements,
The labelling requirements of the former TGO 37(which has now sunset), and,
Standards and requirements contained within the guidelines for the evaluation of disinfectants.


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 12 March 2019

Pharmig News #74

A new edition of Pharmig News has been published. In the latest issue:
  • The hidden problems with relaundering microfibre mops by Karen Rossington
  • Endotoxin hot topics and issues by Ruth Noé and Julie Roberts
  • Validation of contact plates for environmental monitoring by Merck KGaA, Darmstadt, Germany
  • Pharmig Membership Survey by Tim Sandle
  • Latest regulatory news
  • And more!
Copies have been sent out. If you would like to see a copy, please email:

Key reference:

Sandle, T. (2019) Pharmig membership survey, Pharmig News, Issue 74, pp9-12

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Monday, 11 March 2019

Out-of-Specification Laboratory Investigations: New Look at an Old Issue

Since 2006, regulatory agencies have produced guidance on conducting OOS investigations. In addition, many laboratories have established internal procedures so that OOS investigations are consistently undertaken. Indeed, the investigation of an OOS should be covered by a Standard Operation Procedure (SOP) and formally documented. The SOP should contain decision tress to ensure that, where possible, the conclusions reached are consistent.

Despite the guidance that is in place, many regulatory cite poor OOS investigations and these features high up on lists of inspectorate findings. Failure to conduct detailed OOS investigations or not producing OOS investigations of sufficient quality regularly features among the top five inspection findings from European Union regulatory agencies and also from the U.S. Food and Drug Administration.

Tim Sandle has taken a fresh look at laboratory OOS investigations in a new article:

This paper takes a look at how OOS are conducted and presents different ways through which OOS investigations can be improved. While the OOS concept discussed is generally more applicable to analytical data than microbiological data, there are aspects in this paper that will be of interest to all laboratory disciplines working in a regulated GMP environment. The paper provides some best practice tips and short case study.

The reference is:

Sandle, T. (2018) Out-of-Specification Laboratory Investigations: New Look at an Old Issue, Journal of GXP Compliance, 22 (6): 1-10

See IVT -

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Sunday, 10 March 2019

Can bacterial expand the genetic code?

The genetic code that creates all life on Earth consists of four nucleotide bases: Adenine, Thymine, Cytosine, and Guanine. In the double-stranded helix of DNA, these bases pair up with each other in a certain way. In recent years, researchers have been able to expand the genetic code with new, synthetic bases.

These novel bases have long chemical names, but they’ve been abbreviated X and Y. They are called xeno nucleic acids or XNAs. It took many years for researchers to figure out how to pair them properly within a genome. Now they’ve been able to do it, opening up many possibilities for creating synthetic organisms. Learn more about the potential uses of such organisms from the video.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 9 March 2019

DNA search engine for microbes

Researchers at EMBL's European Bioinformatics Institute (EMBL-EBI) have combined their knowledge of bacterial genetics and web search algorithms to build a DNA search engine for microbial data. The search engine, described in a paper published in Nature Biotechnology, could enable researchers and public health agencies to use genome sequencing data to monitor the spread of antibiotic resistance genes. By making this vast amount of data discoverable, the search engine could also allow researchers to learn more about bacteria and viruses.

The search engine, called Bitsliced Genomic Signature Index (BIGSI), fulfils a similar purpose to internet search engines, such as Google. The amount of sequenced microbial DNA is doubling every two years. Until now, there was no practical way to search this data.
This type of search could prove extremely useful for understanding disease. Take, for example, an outbreak of food poisoning, where the cause is a Salmonella strain containing a drug-resistance plasmid (a 'hitchhiking' DNA element that can spread drug resistance across different bacterial species). For the first time, BIGSI allows researchers to easily spot if and when the plasmid has been seen before.

Google and other search engines use natural language processing to search through billions of websites. They are able to take advantage of the fact that human language is relatively unchanging. By contrast, microbial DNA shows the imprint of billions of years of evolution, so each new microbial genome can contain new 'language' that has never been seen before. The key to making BIGSI work was finding a way to build a search index that could cope with the diversity of microbial DNA.


Phelim Bradley, Henk C. den Bakker, Eduardo P. C. Rocha, Gil McVean, Zamin Iqbal. Ultrafast search of all deposited bacterial and viral genomic data. Nature Biotechnology, 2019; 37 (2): 152 DOI: 10.1038/s41587-018-0010-1

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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