Wednesday 31 January 2018

Antimicrobial Resistance

Antimicrobial Resistance (AMR) is the ability of microorganisms to resist antimicrobial treatments, especially antibiotics. AMR is a natural phenomenon but an accumulation of factors, including excessive and inappropriate use of antimicrobial medicines on humans and animals and poor hygiene or infection control practices, transformed AMR into a serious threat to public health worldwide.

News from the European Commission:

AMR not only has a direct impact on human and animal health - due to the failure in the treatment of infectious diseases - but also carries a heavy economic cost.

AMR is already responsible for an estimated 25,000 deaths per year in the EU. Current worldwide mortality from AMR is estimated at 700,000 deaths per year. Inaction is projected to cause yearly millions of deaths globally and by 2050 AMR has the potential to become a more common cause of death than cancer.

It also has wide impacts on the economy, with higher costs of treatments and economic losses due to reduced productivity caused by sickness. In the EU alone it is estimated that AMR annually costs EUR 1.5 billion in healthcare costs and productivity losses. The World Bank warns that, by 2050, drug-resistant infections could cause global economic damage on a par with the 2008 financial crisis.

AMR spreads through global tourism, transfer of patients between healthcare facilities within and from outside the EU, and through trade in food and animals.

It is an important global economic and a societal challenge that can't be tackled by countries or public administrations alone. Therefore, the problem needs a comprehensive "One Health" approach to it. That means that a holistic, multi-sectorial approach, involving many different sectors (public health, food safety, bio-safety, environment, research and innovation, international cooperation, animal health and welfare as well as non-therapeutic use of antimicrobial substances) is needed to tackle this complex problem.

Monday 29 January 2018

Microbiological Test Data - Assuring Data Integrity

Ed Tidswell and Tim Sandle have written a paper on data integrity and microbiology:

Marketed drugs and devices possess specifications including critical microbiological quality attributes purposed to assure efficacy and patient safety. These attributes are legislated requirements intended to protect the recipient patient. Sampling, microbiological testing, interpretation of data for final products, raw materials and intermediates all contribute to a cohesive assessment in the assurance of finished product quality. Traditional culture-based microbiological methods possess inherent and unavoidable variability, recognized by the compendia and which might lead to erroneous conclusion pertaining to product quality. Such variability has been associated and intrinsically linked with data integrity issues; manufacturers have subsequently been encouraged by regulatory authorities to introduce multiple microbiologists or checks to prevent such issues. Understanding microbiological variability is essential such that genuine data integrity issues are identified. Furthermore, a range of meaningful preventative strategies are feasible beyond increasing the capacity of the quality control microbiological laboratory. This short review describes the legislative requirements, inherent microbiological variability and realistic actions and activities that genuinely assure patient safety.

The paper has been published by the PDA.

The reference is:

Tidswell, E. C. and Sandle, T. (2017) Microbiological Test Data - Assuring Data Integrity, PDA J Pharm Sci Technol; doi:10.5731/pdajpst.2017.008151

Thursday 25 January 2018

Cases of superbug Clostridium difficile increase

The most troubling cases of C. difficile infection, termed multiple recurring C. difficile infections (mrCDI), are becoming more common, according to a new university research study.

The study comes from the University of Pennsylvania School of Medicine and it highlights a concern within the U.S. healthcare network (made up of 40 million patient records). The data was drawn from a large, nationwide health insurance database. The big data analysis not only informs about the general Clostridium difficile rate (which affects over half a million U.S. citizens each year), it shows the extent of recurrent infections.

Clostridium difficile infection refers to a symptomatic infection due to the spore-forming bacterium. By being spore forming the organism is hard to kill. Symptoms of infection can include watery diarrhea, fever, nausea, and abdominal pain. Further complications can include pseudomembranous colitis, toxic megacolon, perforation of the colon, and sepsis.

Multiple recurring C. difficile infections raise concerns because recurrent infections increase the risk of death for already vulnerable patients. Reoccurrence also signals that attempts at eradication of this infection are failing. Furthermore recurrent cases also tend to involve more virulent strains of the bacterium. These risks have been described in an article for the journal Anaerobe headed “A case of multiple recurrence of Clostridium difficile infection with severe hematochezia in an immunocompromised host.”

The propensity of recurrence occurs in 15 to 35 percent of patients who initially respond to antimicrobial therapy. Due to the need to switch to different antibiotics, and the added complication of antibiotic resistance, the recurrent cases are especially difficult to treat and they contribute to significant morbidity and mortality and increased health care expenditures. Antibiotics called metronidazole, vancomycin, and fidoxamicin are often used to treat infections, but resistance can arise.

According to the new analysis, the reason for the sharp rise in mrCDI's incidence is uncertain; what is clear is that the cases are growing (rising by 43 percent over a recent ten year period). What the report does highlight is need for new approaches to treatment. An example of this is with fecal microbiota transplantation, where beneficial intestinal bacteria from one patient are infused into another to help out-compete the infective C. difficile.

This needs more study, however, according to Professor James D. Lewis from the University of Pennsylvania: “While we know that fecal microbiota transplantation is generally safe and effective in the short term, we need to establish the long term safety of this procedure."
Posted by Dr. Tim Sandle

Tuesday 23 January 2018

59th Session of the European Pharmacopeia Commission

The European Pharmacopoeia (Ph. Eur.) Commission adopted 11 new monographs at its 159th Session, which took place in Strasbourg on 21-22 November 2017:

A monograph elaborated under the P4 procedure, Rotigotine (3014). This procedure applies to substances still under patent protection.

The first monograph on a multisource monoclonal antibody, Infliximab concentrated solution (2928); a dedicated press release will be published soon.

Monographs on Phenoxymethylpenicillin, benzathine (2636), Zoledronic acid monohydrate (2743), Imidacloprid for veterinary use (2924), Podophyllotoxin (2750), Sulfobutylbetadex sodium (2804), Concentrated solutions for haemofiltration and haemodiafiltration (2770), Digitalis purpurea for homoeopathic preparations (2705), Lightyellow sophora root (2440), Gastrodia rhizome (2721) and Phytomenadione, racemic (3011).


Posted by Dr. Tim Sandle

Monday 22 January 2018

Application of ISO 14644 Parts 1 and 2 for cleanroom contamination control

Cleanrooms are highly controlled environments, defined the air quality, and where certain physical and microbiological requirements need to be met.  Air quality is achieved through a combination of airborne particulate control, such as through High Efficiency Particulate Air (HEPA) filters; high fresh air rates (air movement and air changes); clean-up (or ‘recovery’) times; pressure differentials, which concerns air direction; temperature and humidity control (where necessary); cleaning and disinfection; and staff behaviors and gowning. The requirements for air quality, and the associated physical aspects designed to achieve this, are contained within the international standard ISO 14644.

To examine the requirements of Parts 1 and 2 of the standard in relation to contamination control in cleanrooms, Tim Sandle has written a chapter for Volume 8 of the ongoing Environmental Monitoring: A Comprehensive Handbook series.

Different types of cleanrooms require different levels of control to achieve the desired level of cleanliness. The required standard of cleanliness of a room will relate to the type of task performed in it and it follows that the more susceptible the product is to contamination, the better (“cleaner”) the standard that is accepted. The chapter explores this principle from the perspective of microbiological risk,

The reference is:

Sandle, T. (2017) Application of ISO 14644 Parts 1 and 2 for cleanroom contamination control. In Moldenhauer, J. (Ed.) Environmental Monitoring: A Comprehensive Handbook, Volume 8, DHI Publoshing / PDA, River Grove, IL, USA, pp3-22

Posted by Dr. Tim Sandle

Sunday 21 January 2018

Webinar - Investigating Sterility Test Failures

New webinar - January 25, 2018

Date: Thursday, 25 January 2018 | Time: 10:00 AM PST, 01:00 PM EST | Duration: 60 Minutes

Sterility testing is widely used in both the medical device and pharmaceutical industries. The pharmacopeia test is the official procedure for testing the sterility of pharmaceutical products. Despite its importance and its widespread use, many people are not aware of the limitations of the sterility test and are unsure how to proceed when a failure investigation occurs.

Instructor: Tim Sandle
Product ID: 503878

Questions to help with this process, like -- "Can the test be invalidated? Is the product rejected? What needs to be investigated? How is root cause established? What need to be done before production can resume?"-- will be answered in this webinar.

Objectives of the Presentation

  • What the sterility test can and cannot demonstrate
  • The causes of sterility test failures
  • The actions required on being notified of a failure, including deviation management and quarantine
  • Best practices for laboratory test investigations
  • Best practices for processing investigations
  • Best practices for aseptic processing investigations
  • Developing a remediation plan including the necessity for media simulation trialsWhy Should you Attend
  • To gain an insight into the best practices for sterility test failure investigations, from a speaker who has presented sterility test failure investigation reports to both FDA and European Medicines Agency inspectors.

Areas Covered

  • History of the sterility test
  • Statistical limitations of the sterility test
  • Actions required by management on being notified of a sterility test failure
  • The importance of genotypic microbial investigation
  • Points to consider for investigating testing, such as cleanroom or isolator operational parameters
  • Reviewing major contamination incidences in process areas that could lead to a sterility failure, from raw materials to wet equipment
  • Detailed forensics for aseptic process investigations, such as reviewing people, processes and equipment
  • How to do put an investigation report together
  • How to test out CAPA through media fills
  • What to do if the investigation is inconclusive
For details, see Online Compliance Panel.

SCREEN United Kingdom Cargo Theft Report Q3 2017

BSI and the National Vehicle Crime Intelligence Service (NaVCIS) have come together to develop a robust report to provide increased visibility into cargo theft threats across the United Kingdom. BSI recorded a total of 296 cargo theft incidents in the United Kingdom during the third quarter of 2017, with nearly 63% of them involving the slash-and-grab tactic and 18% involving theft from hard-sided trucks. BSI recently held a webinar to review our findings, including:

Q3 United Kingdom cargo theft analysis
County breakdown of the top cargo theft threats in the United Kingdom
Top targeted commodities, methods and locations of thefts, and areas of concern

To access the webinar recording, please click here.

To download the newly released report, click here.

Posted by Dr. Tim Sandle

Friday 19 January 2018

Are Phages Our Best Bet Against Antibiotic-Resistant Bacteria?

Bacteriophages, or simply phages, are viruses that infect and replicate within bacteria, and they hold considerable potential for combatting antibiotic-resistance and other threats to human health. Timed with the hundredth anniversary of their discovery, a new review published in the British Journal of Pharmacology examines the challenges and opportunities of developing phages as health-promoting, commercially-viable biopharmaceuticals.

In the review, Amanda Forde, PhD, and Colin Hill, PhD, of the APC Microbiome Institute at University College Cork, in Ireland, note that phages have complex relationships with bacteria in the gut that could affect health and disease. “Through an intricate 'predator-prey' strategy, phages have the ability to alter the microbial balance within an ecosystem, and given that they are the most abundant biological entities on earth, it would be odd to ignore or underestimate their power and potential,” said Dr. Forde. She explained that phages outnumber their bacterial prey by a factor of 10 to 1, and that they have been proposed as the agents of change in recipients of faecal microbiota transplantations used to treat resistant or recurring bowel disease.

“We tend to think of phages as nature's 'nano-machines', self-assembling complex biological survival machines capable of replicating faster than any other biological agent,” said Dr. Hill. “They are highly diverse, highly dynamic, and highly specific to their targets, and as antibiotic-resistant 'superbugs' continue to emerge around the world, they may be among our best allies in the future.”

Despite having been discovered a century ago, their use in clinical therapy continues to encounter several challenges. “One of the challenges lies in the fact that more than 90% of phage populations are as yet unidentified, and therefore considered to be the 'dark matter' of the biological world,” said Dr. Hill. “Coupled with manufacturing challenges, regulatory hurdles and the need for clinical validation, the path to pharma may seem long, but researchers are heading in the right direction.”

Phages were used for more than 75 years as therapy in Eastern Europe, but they fell out of favour in the western world when antibiotics were discovered. They are now becoming attractive again because of the rise in antibiotic resistance. A unique selling point is their host specificity, meaning little or no collateral damage to neighbouring ('good') bacteria, and they do not drive the development of resistance in non-target bacterial species.

“Whilst regulated phage therapy may take some time, it has been highly successful in recent 'compassionate' cases where patients’ lives were on the line,” said Dr. Forde. “But for regulated interventions, we need to play the waiting game as more genomic, physiological, pharmacological, and clinical data are gathered. And wait we will.”
Posted by Dr. Tim Sandle

Thursday 18 January 2018

Single sand grain harbors up to 100,000 microorganisms

Just imagine, you are sitting on a sunny beach, contentedly letting the warm sand trickle through your fingers. Millions of sand grains. What you probably can't imagine: at the same time, billions upon billions of bacteria are also trickling through your fingers. Between 10,000 and 100,000 microorganisms live on each single grain of sand, as revealed in a new study.

It has long been known that sand is a densely populated and active habitat. Now David Probandt and his colleagues have described the microbial community on a single grain of sand using modern molecular methods. To do this, they used samples taken from the southern North Sea, near the island of Helgoland, off the German coast.

The bacteria do not colonize the sand grains uniformly. While exposed areas are practically uncolonized, the bacteria bustle in cracks and depressions. "They are well protected there," explains Probandt. < "When water flows around the grains of sand and they are swirled around, rubbing against each other, the bacteria are safe within these depressions." These sites may also act as hiding grounds from predators, who comb the surface of the sand grains in search of food.

However, the diversity of the bacteria, and not just their numbers, is impressive. "We found thousands of different species of bacteria on each individual grain of sand," says Probandt.

Some bacteria species and groups can be found on all investigated sand grains, others only here and there. "More than half of the inhabitants on all grains are the same. We assume that this core community on all sand grains displays a similar function," explains Probandt. "In principle, each grain has the same fundamental population and infrastructure." We can therefore really discover a great deal about the bacterial diversity of sand in general from investigating a single grain of sand.

Sand-dwelling bacteria play an important role in the marine ecosystem and global material cycles. Because these bacteria process, for example, carbon and nitrogen compounds from seawater and fluvial inflows, the sand acts as an enormous purifying filter. Much of what is flushed into the seabed by seawater doesn't come back out.


David Probandt, Thilo Eickhorst, Andreas Ellrott, Rudolf Amann, Katrin Knittel. Microbial life on a sand grain: from bulk sediment to single grainsThe ISME Journal, 2017; DOI: 10.1038/ismej.2017.197

Posted by Dr. Tim Sandle

Wednesday 17 January 2018

How to comment on Draft EU GMP Annex 1

News from the European Medicines Agency:

Targeted stakeholders consultation on the revision of annex 1, on manufacturing of sterile medicinal products, of the Eudralex volume 4

Period of consultation

From 20 December 2017 to 20 March 2018.

Objective of the consultation

Annex 1 was first published in 1971, since then it has undergone a number of targeted updates but, until now it has not undergone a full review. This revision is intended to add clarity, introduce the principles of Quality Risk Management to allow for the inclusion of new technologies and innovative processes and to change the structure to a more logical flow. Key changes are:
  • Introduction of new sections: scope, utilities, Environmental and process monitoring sections and glossary 
  • Introduction of QRM Principles 
  • Restructured to give more logical flow 
  • Added detail to a number of the previous sections to provide further clarity. 

In order to maintain the global alignment of standards, achieving at the same time assurance for the highest quality, the proposed revised version was prepared in cooperation with WHO and PIC/S. The document will be subject to parallel public consultation by WHO and PIC/S.

How to submit your contribution

Please provide feedback using the template enclosed sending it to

They can also be sent by post to Directorate-General for Health and Food Safety, Unit SANTE B/4, BE-1049 Brussels. The subject line of the letter or email should contain the reference "Targeted Public Consultation – Revision of annex 1 of EU GMP Guide".

When submitting your response, please include your name and e-mail address and specify if you are responding as an individual or as a representative of an organisation. If you represent an organisation, please indicate its name and category (company/business; public authority (local, regional, national, international); NGO; patient organisation; other).

If you represent a company, please state whether it falls within the EU definition of a small and medium-sized enterprise (i.e. less than €50 million annual turnover and fewer than 250 employees).

If your organisation is registered in the Transparency Register, please indicate your Register ID number at the beginning of your contribution.

The consultation document

The consultation document can be downloaded here.

The template for comments can be downloaded here.

Contact details

Responsible service: Directorate-General for Health and Food Safety - Unit B4 - Medical Products: quality, safety, innovation.


Any queries about the public consultation should be sent to this mailbox.

Saturday 13 January 2018

Reclassification of Propionibacterium acnes

The bacterium Propionibacterium acnes has been reclassified as Cutibacterium acnes, based on discrepancies between the phylogenetic signals of 16S rRNA gene sequence analysis and high-resolution core-genome analysis.

The former P. acnes is a bacterium associated with the outer layers of the human skin and it has an association with sterility test failures. 

The reference for the change is:

Scholz, C.F.P. and Kilian, M. (2016) The natural history of cutaneous propionibacteria, and reclassification of selected species within the genus Propionibacterium to the proposed novel genera Acidipropionibacterium gen. nov., Cutibacterium gen. nov. and Pseudopropionibacterium gen. nov., International Journal of Systematic and Evolutionary Microbiology, 66, 4422–4432

Here is the abstract to the paper:

The genus Propionibacterium in the family Propionibacteriaceae consists of species of various habitats, including mature cheese, cattle rumen and human skin. Traditionally, these species have been grouped as either classical or cutaneous propionibacteria based on characteristic phenotypes and source of isolation. To re-evaluate the taxonomy of the family and to elucidate the interspecies relatedness we compared 162 public whole-genome sequences of strains representing species of the family Propionibacteriaceae. We found substantial discrepancies between the phylogenetic signals of 16S rRNA gene sequence analysis and our high-resolution core-genome analysis. To accommodate these discrepancies, and to address the long-standing issue of the taxonomically problematic Propionibacterium propionicum, we propose three novel genera, Acidipropionibacterium gen. nov., Cutibacterium gen. nov. and Pseudopropionibacterium gen. nov., and an amended description of the genus Propionibacterium. Furthermore, our genome-based analyses support the amounting evidence that the subdivision of Propionibacterium freudenreichii into subspecies is not warranted. Our proposals are supported by phylogenetic analyses, DNA G+C content, peptidoglycan composition and patterns of the gene losses and acquisitions in the cutaneous propionibacteria during their adaptation to the human host.

The paper can be found online here.

Posted by Dr. Tim Sandle

Thursday 11 January 2018

Overuse of antibiotics in farming is a major new threat to human health

Antibiotics that has spilled from farms into the natural environment may be a bigger factor in spreading resistance to life-saving drugs than previously thought, U.N. report says.

The overuse of antibiotics in farming has been highlighted as one of the biggest emerging threats to human health, spreading resistance to vital drugs and endangering millions of lives.

Antibiotics used on farms can spill over into the surrounding environment, for instance through water run-off and slurry, according to a report from the UN’s environment body, with the potential to create resistance to the drugs across a wide area.

This environmental diffusion of powerful medicines, to which bacteria are increasingly gaining resistance, is rendering even the drugs of last resort ineffective in human treatment, and may be a bigger factor in spreading resistance than had been thought. Previous concerns focused on resistance to the drugs among livestock and farm workers, but the UN report says the problem goes much further and is much more dangerous.

From The Guardian - read more here.

Tuesday 9 January 2018

Pharmig conference report

The new to invest in new technologies and a call for a new paradigm for approaching risk assessment were the keynote messages from the 2017 Pharmig conference, which focused on making medicines safe for patients.

Despite innovations in rapid microbiological methods the pharmaceutical sector has been slow to adopt the latest technologies; moreover, the approach to assessing the risks to products is too often rooted in poor science and an over-reliance upon scoring every tiny detail with an arbitrary number. These were the messages delivered by a pharmaceutical regulator and one of the world’s foremost pharmaceutical microbiologists.

The Pharmaceutical Microbiology Interest Group (Pharmig) hosts an annual conference each year in the U.K. This year’s event took place at Heythrop Park, part Grade II listed Baroque building designed for the Duke of Shrewsbury, and part modern conference center.

The conference opened with addresses from two former chairs of Pharmig: Sharon Johnson and David Begg. Begg called on the industry not to forget what really matters - protecting patients; and Johnson queried why progress with the adoption of rapid methods was so slow.
David Begg  a former medicines inspector  addresses the 2017 Pharmig conference.
David Begg, a former medicines inspector, addresses the 2017 Pharmig conference.
Need for a less conservative pharmaceutical industry
The call for the pharmaceutical industry to be less conservative with the adoption of rapid microbiological methods came from healthcare regulator Andrew Hopkins (the pertinent points from his presentation are discussed in the article “Rapid methods needed to help safety of medicines”). Hopkins stressed that better dialogue was required between regulators and pharmaceutical manufacturers, and he outlined a forum that can be used for this purpose.
One of the exhibition stands at the Pharmig conference  with a display of the special clothing requi...
One of the exhibition stands at the Pharmig conference, with a display of the special clothing required to access production areas.
The need for a renewed focus on risk assessment came from Dr. Edward Tidswell (Merck-U.S.), who is also an expert in how microorganisms adhere to surfaces and co-editor of the book “Aseptic and Sterile Processing: Control, Compliance and Future Trends”. Dr. Tidswell, in conjunction with Kevin O’Donnell, who represents the Irish regulator agency the HPRA, said that too many risk assessments are based on a lack of data and use a poorly conceived scoring system. Called out for greatest criticism was ‘Failure Modes and Effects Analysis’ (FMEA), a risk tool commonly used in the engineering sector.
Dr. Edward Tidswell address the 2017 Pharmig conference.
Dr. Edward Tidswell address the 2017 Pharmig conference.
New paradigm for risk management
Instead, Dr. Tidswell said, quantitative risk management was needed - real-time data and lots of it. Only through big data analytics, the pharmaceutical microbiologist stated, can risks of microbial contamination transfer to a pharmaceutical product be truly understood and quantified. For this to work, and in a link back to the presentation made by Hopkins, a greater adoption of rapid methods is needed. Hence both new approaches to risk assessment and rapid methods are needed for the digital transformation of pharmaceutical microbiology.
Examples of rapid microbiological methods on show at the Pharmig conference  including real-time bio...
Examples of rapid microbiological methods on show at the Pharmig conference, including real-time biologica air-samplers.
Another presentation of note was delivered by Professor Willy Verstraete of the University of
Ghent, Belgium. This presentation looked at ecological microbiology and how understanding microbial communities better is the basis for better environmental control, especially in relation to agriculture. Here biotechnology, such as the use of nitrogen-utilizing bacteria in bioreactors, can be used for such innovations as microbial protein to be used as a meat substitute. For more on Professor Verstraete’s treatise see the article “Will microbial protein replace meat on the table?"
New microbial contamination concerns
Contamination of pharmaceutical products with water-borne organisms was a theme addressed in two presentations. The first was a case study outlined by Geert Verdonk, from the German pharmaceutical giant Merck. The second was a regulatory perspective given by Dr. John Metcalfe, from the U.S. Food and Drug Administration (FDA).
David Keen  chair of Pharmig  addresses the 2017 conference.
David Keen, chair of Pharmig, addresses the 2017 conference.
In these presentations that growing regulatory focus on the organisms that form the Burkholderia Cepacia Complex was detailed, especially in relation to non-sterile pharmaceutical products. Burkholderia Cepacia Complex is a group of some twenty organisms; bacteria that are naturally resistant to many common antibiotics and thereby posing a public health hazard. If pharmaceutical products are contaminated with such organisms, then based on the patient population and the total bioburden, this would pose a risk of serious illness.

According to Dr. Metcalfe it is beholden upon pharmaceutical manufacturers to stablish procedures to prevent these objectionable microorganism contaminating of drug products. This includes having adequate procedures to assure adequate quality of incoming materials; ensuing processes are of sanitary design with appropriate maintenance and cleaning of equipment. In addition there should be production and storage time limitations, supported by the monitoring of environmental conditions.
Delegates meeting with exhibitors at the Pharmig 2017 conference.
Delegates meeting with exhibitors at the Pharmig 2017 conference.
Sanitary design was discussed by another presenter, Neil Lewis who is the Global Household Care Microbiologist at Proctor and Gamble. This looked at how alternative methodologies can be used to assess the cleanliness of equipment, arguing that legacy approaches to do not adequately address microbial risks.
New technologies on the horizon
The new technology theme was continued by Dr. Mark Sutton, who works for Public Health England. Dr. Dutton has developed an alternative means for assessing biodecontamination of clean areas. Instead of the sometimes imprecise method of adding bacterial spores onto strips of paper or stainless steel to assess microbial kill, Dr. Sutton is proposing an enzymatic test using thermostable Adenylate Kinase. This enzyme is found in all cells and it plays a role in cellular energy homeostasis.

Other presentations took different directions. Les Meader, who runs two companies - Omnia CS and Foresight Innovations Limited, discussed why human error occurs and how understanding this can be applied to pharmaceutical and healthcare manufacturing. Understanding human psychology, Meader argued, is necessary if processes are to be designed in an optimal way as so to reduce people related mistakes.

The theme of training was central to new a digital training module developed by Pharmig for those tasked with cleaning and disinfection. The online platform uses digital technology and e-learning to reinforce best practices. The module was previewed by Rachel Blount and Laura Guardi, both representing Pharmig.
Rachel Blount and Laura Guardi presenting a new interactive training video.
Rachel Blount and Laura Guardi presenting a new interactive training video.
Brexit and regulations
Andrew Hopkins gave a second presentation addressing a concoction of topics, from ways to produce pharmaceutical grade water (reverse osmosis or distillation) to Brexit (the impact of regulations on making medicines in the U.K.) His central theme was, however, Good Manufacturing Practice (GMP) and the forthcoming changes to the guidance for sterile products (Annex 1 to European Union GMP). The new guidance foster the need for a formal microbial contamination risk assessment.

The take-home messages from the conference, chaired by GlaxoSmithKline expert microbiologist David Keen, were that more can be done to protect patients in the production of safe medicines. For this, quality risk management and new technologies are the tools required to achieve this.

Written by Dr. Tim Sandle

Monday 8 January 2018

Microbiological Aspects of Cleaning Validation

Cleaning validation refers to the methodology applied to give the assurance that a cleaning process has removed residues and contaminants from a piece of equipment or machinery. Residues may be microorganisms; active pharmaceutical ingredients; other process chemicals, such as buffers; cleaning agents themselves (such as detergents); or microbiological culture media (in relation to aseptic process simulations). Assurance relating to cleaning validation refers to both the effectiveness of the cleaning process and the consistency at which cleaning is applied. As with any other type of validation, the ‘validation’ aspect refers to providing documented evidence that that the acceptance criteria have been met.

Tim Sandle has written a new paper. Here is an extract:

Cleaning is assessed based on the level of residues that remain, either those directly found on the equipment or those indirectly contained within the final rinse after water has passed through or over the equipment. Whether the residues remaining have been reduced to a satisfactory low level is based on predetermined acceptance criteria (2). The levels need to be sufficient low to ensure that the next product manufactured is not compromised by waste or contamination from the previous product (that is in ensuring that cross-contamination does not occur). An additional concern is with the microbial bioburden.

With equipment cleaning, this can be undertaken using an automated process (such as CIP - Clean-in-Place technologies) or manually (which often involves the physical removal of the equipment and its transport to a wash-bay; sometimes called COP - Clean-Out-of-Place). In general manual cleaning should be avoided due to process and operator variability. Where manual cleaning cannot be avoided, due to technical limitations, robust controls need to be in place to ensure consistency.

The chemical verification of cleaning validation is relatively well described. What is often less clear, and some contentious in terms of whether it needs to always be included, is the microbiological aspect. Important to the microbiological aspect are microorganisms themselves (a direct hazard) and the presence of residues that potentially provide a microbial growth source, should contamination be present or contamination occur during the hold period (an indirect hazard).

To evaluate these microbiological risks a sound microbiological sampling plan is required. The emphasis on sampling is important since microorganisms cannot be introduced into the process. This is unlike a chemical assessment where equipment can be deliberately soiled with a residue to test out cleaning efficacy. Microbial controls should not be introduced into the cleaning process. This article assesses the risks from microorganisms and the cleaning requirements necessary to achieve microbial control.

The reference is:

Sandle, T. (2017) Microbiological Aspects of Cleaning Validation, Journal of GxP Compliance, 21 (5): 1-12, at:

To find out more please contact Tim Sandle at:  

Friday 5 January 2018

Meningococcal vaccine could protect against 91 percent of targeted bacterial strains

Up to 91 percent of bacterial strains causing a common type of invasive serogroup B meningococcal disease in children and young adults are likely to be covered by a four-component vaccine called MenB-4C (Bexsero), according to laboratory studies conducted by investigators at the federal Centers for Disease Control and Prevention (CDC) and at GlaxoSmithKline, manufacturer of the vaccine. The work was published recently.

Researchers used a laboratory test called the Meningococcal Antigen Typing System (MATS) to study the coverage potential of the MenB-4C vaccine, which was approved by the Food and Drug Administration in January 2015 for use in individuals ages 10-25 years. The vaccine contains 4 antigens to prevent invasive meningococcal disease caused by the serogroup B form of the bacteria Neisseria meningitidis: factor H binding protein (fHBP), Neisserial heparin binding protein (NHBA), Neisserial adhesin A (NadA) and PorA-containing outer membrane vesicles. These antigens are found on the bacteria, and vaccination with them induces an immune response in the recipients that helps protect them from infection by the bacteria that carry the antigens. In the United States in 2015, serogroup B strains of the bacteria caused approximately 40 percent of invasive meningococcal disease in all age groups, including adolescents, and over 60 percent of cases in infants aged less than one year.

Researchers tested 442 N. meningitidis serogroup B samples collected by CDC from 2000 to 2008. The MATS test predicted that 91 percent of these bacterial strains causing meningococcal disease in the United States would be covered by the MenB-4C vaccine, with an estimated coverage ranging from 88 percent to 97 percent each year.

More than half of the covered strains could be targeted by two or more antigens in the vaccine, the investigators found. NHBA covered 83 percent of the strains, fHBP covered 53 percent of the strains, PorA covered 5.9 percent of the strains and NadA covered 2.5 percent of the strains.


Gowrisankar Rajam, Maria Stella, Ellie Kim, Simon Paulos, Giuseppe Boccadifuoco, Laura Serino, George Carlone, Duccio Medini. Meningococcal Antigen Typing System (MATS)-Based Neisseria meningitidis Serogroup B Coverage Prediction for the MenB-4C Vaccine in the United StatesmSphere, 2017; 2 (6): e00261-17 DOI: 10.1128/mSphere.00261-17

Posted by Dr. Tim Sandle

Thursday 4 January 2018

Tracking how deadly 'superbugs' travel could slow their spread

Using data from a 2008 outbreak of one of the most-feared "superbugs," and modern genetic sequencing techniques, a team has successfully modeled, and predicted, the way the organism spread between and within dozens of healthcare facilities.

The approach can tell if the bug is spreading within a hospital, nursing home or long-term acute care hospital -- or if a new patient transferred from another facility has brought it there.

In other words, if fighting superbugs is like a horror movie, the approach can tell if the call is coming from inside the house, or if the killer is lurking outside and about to barge through the door.

And just like in a horror movie, getting an answer quickly can guide what kinds of barricades and weapons health professionals should use against the villain.

The approach, published in Science Translational Medicine , combines current epidemiological approaches with whole-genome sequencing -- spelling out the entire DNA sequence of bacteria from each infected patient.

This makes it possible to use the tiny changes in superbug DNA -- the kind of mutations that happen naturally over time -- to track their spread within and between healthcare facilities.


Evan S. Snitkin, Sarah Won, Ali Pirani, Zena Lapp, Robert A. Weinstein, Karen Lolans, Mary K. Hayden. Integrated genomic and interfacility patient-transfer data reveal the transmission pathways of multidrug-resistant Klebsiella pneumoniae in a regional outbreakScience Translational Medicine, 2017; 9 (417): eaan0093 DOI: 10.1126/scitranslmed.aan0093

Posted by Dr. Tim Sandle

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