Artificial Intelligenсe to Improve Cancer Diagnosis in NHS

British Prime Minister Theresa May is expected to challenge the National Health Service, health charities and artificial intelligence developers to work to together in order to transform how chronic diseases are diagnosed. Commentary by Tim Sandle.

Artificial Intelligenсe to Improve Cancer Diagnosis in NHS by Tim Sandle on Scribd

3-D structure of 1918 influenza virus

Virus-like particles (VLPs) are protein-based structures that mimic viruses and bind to antibodies. Because VLPs are not infectious, they show considerable promise as vaccine platforms for many viral diseases, including influenza. Realizing that fine details about influenza VLPs were scant, a team of researchers who specialize in visualizing molecular structures developed a 3D model based on the 1918 H1 pandemic influenza virus. They say their research, which appears online in Scientific Reports, could benefit VLP vaccine projects, targeting a range of viruses from HIV to Ebola and SARS coronavirus. The research was conducted by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Other researchers had produced VLPs for 1918 H1 influenza that successfully protected animals from different influenza viruses. The NIAID group prepared hundreds of such VLP samples and analyzed their structure with a technique called cryo-electron microscopy, which quick-freezes samples with glass-like clarity. They then sliced through those VLP 3D structures -- like slicing through a loaf of bread -- to analyze their internal structure, using computers to document the size and placement of key molecules. After averaging all their data, the group then created a 3D 1918 influenza VLP model.

The scientists found that about 90 percent of the VLPs are hemagglutinin (HA) proteins (by weight) found on the VLP surface. In contrast, HAs comprise less than half of the viral proteins of natural influenza viruses. The number and location of HA molecules may influence the efficacy of VLP vaccines, influencing the binding of antibodies to specific epitopes on the HA protein. Those antibodies can similarly bind live influenza viruses, preventing them from infecting cells.

The research group, in NIAID's Laboratory of Infectious Diseases, is continuing its work by comparing its VLP data to data from other natural influenza viruses. They believe the more that is understood about the molecular organization of influenza VLPs, the better scientists will be able to develop effective seasonal and universal influenza vaccines.

See: Dustin M. McCraw, John R. Gallagher, Udana Torian, Mallory L. Myers, Michael T. Conlon, Neetu M. Gulati, Audray K. Harris. Structural analysis of influenza vaccine virus-like particles reveals a multicomponent organization. Scientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-28700-7
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Diagnostic connectivity to combat antimicrobial resistance

The British government has entered into a partnership with FIND, a global non-profit dedicated to accelerating the development of diagnostic tests for diseases. This is to introduce digital technologies to combat the antimicrobial resistance problem.

The partnership, following the signing of a Memorandum of Understanding, establishes a three-year project focusing on connecting data from patients’ diagnostic test results into various national antimicrobial resistance surveillance program in low- and middle-income countries. This digital information will be to help address the rising problem of drug resistant infections.

The announcement about the collaboration was made on May, 22 2018 at the 71st World Health Assembly, which took place in Geneva, Switzerland. The project is being funded from U.K. Government’s Global Antimicrobial Resistance Innovation Fund. Here the British state will work with the Foundation for Innovative New Diagnostics (FIND).

The aim of the project, for the connectivity for diagnostics, is to improve worldwide surveillance of antimicrobial resistance. Here FIND and partner bodies will produce alternative tools and new solutions to connect information from antimicrobial resistant-related diagnostic testing of patients and to input the analyzed information into national surveillance programs operating in low- and middle-income countries. The aim is to greatly extend the scope of existing programs so they include routine hospital and community data.

The growing menace of antibiotic resistance presents the single most significant threat faced by the global population. The urgency is with profiling patterns of resistance, so that epidemiological patterns can be assessed, and with the development of new antibiotics. The risk is very real: human populations face the very real risk of a future without antibiotics. The implications of this are that life expectancy could fall due to people dying from diseases that are readily treatable today. For example, around 700,000 deaths each year are caused by drug-resistant pathogens worldwide.

The FIND strategy is that diagnostics plays an important role in helping to minimize the proliferation of drug-resistant bacteria, viruses, parasites and fungi. By using appropriate diagnostic tests, medical professionals can identify disease-causing pathogens and use this information to determine the presence of drug resistance. This is only possible through comprehensive databases, assessed using big data analytics.

An example is with drug resistant tuberculosis, here FIND are helping to develop better tests for case detection & drug susceptibility testing (sputum); improved tests for detection and triage (non-sputum); and latent-to-active prediction tests. These are often alternatives to lengthy culture based methods, offering rapid microbiological alternatives aimed at improved accuracy and faster time-to-result.

According to Catharina Boehme, who is the CEO of FIND: “Diagnostics are critical to tracking and monitoring diseases and the spread of drug resistance…Connecting diagnostics to surveillance systems at various levels from local to global will allow surveillance to be strengthened in LMICs – where the burden of infectious diseases is highest but data are currently limited.”

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Pharmig publications

Factsheets cleanroom isolates

Standard microbiology text books are biased to medical bacteria. These factsheets provide pharmaceutical microbiologists with details on the most common isolates from pharmaceutical cleanrooms.

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.

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.

See: https://www.pharmig.org.uk/en/product/a-series-of-8-fact-sheets-on-cleanroom-environmental-isolates-november-2016/

Factsheets on fungi

Regulators have stated that knowledge of fungal identification is weak in microbiology laboratories, and many inspectors expect fungi to be identified as part of microbial contamination tracking. The problem is, few text books focus on the most common cleanroom isolates.

Pharmig has addressed a gap by profiling the most common fungi found in cleanrooms (based on FDA recalls) and presenting full colour guides to the cultivation and identification of these fungi.  Included with the macroscopic and microscopic images is detailed advice on where these fungi are found and what the implications for their recovery means.

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.

See: https://www.pharmig.org.uk/en/product/a-series-of-8-fact-sheets-on-pharmaceutically-important-fungi-2/

Rapid and alternative methods

Most microbiologists are seeking to invest in and develop rapid or alternative microbiological methods, in order to produce more accurate and faster results. There are also advantages in terms of automation and data integrity.

Finding out about the different technologies and then selecting between methods can be challenging. This publication provides an overview of different types of technologies and profiles many of the current methods available.

The guide also provides microbiologists (and their management chain) with guidance on selecting and qualifying methods (running the IQ, OQ and PQ spectrum). Also included is detail on how to build a case for justifying a method, considering factors like return on investment.

See: https://www.pharmig.org.uk/en/product/pdf-publication-on-rapid-alternative-microbiological-methods-joint-publication-between-pharmig-ctpa/

Factsheets on objectionable organisms

Objectionable organisms is a buzz phrase in the pharmaceutical sector, prompted by a push from regulators to consider those microorganisms beyond those described in the pharmacopeia as specified organisms that might pose a risk to products.

This series of factsheets describes the criteria for determining whether an organism is objectional or not (looking at things like product risk profiles and the patient population), and presents profiles of many common objectionales. These organisms have been selected based on their commonality to the environment and appearance in recall observations from inspectors.

The fact sheets use colour photographs illustrating growth on agar and by Gram-stain. These are supported by facts relating to the organism’s profile and methods for identification.

The sheets are presented in a pack and together provide a unique, informative and colourful guide to an important area of quality control microbiology.

See: https://www.pharmig.org.uk/en/product/a-series-of-8-fact-sheets-on-major-objectionable-organisms/

Factsheets on Microbial Limits Test organisms

The Microbial Limits Test is the mainstay of many pharmaceutical microbiology laboratories. While the test is common there are challenges, such as identifying and characterising the specific microorganisms described in the pharmacopeia.

These factsheets are designed to act as a training aid for new staff, and an aide memoire for more experienced staff. The sheets use colour photographs to illustrate growth on agar and by Gram-stain. Each organism is additionally profiled, with information relating to the organism’s profile and risks to the patient.

The sheets are laminated and presented in a pack and together provide a unique, informative and colourful guide to an important area of quality control microbiology.

See: https://www.pharmig.org.uk/en/product/a-series-of-8-microorganisms-fact-sheets/

Best Practices in Microbiological Documentation – Electronic Pack One

Microbiology laboratories contain many computerised systems, SOPs, protocols and forms. When setting up a microbiology laboratory, generating the required documentation is a huge task. This Pharmig pack provides all of the necessary templates you’ll need in a downloadable and editable format.

The pack includes:

·         Training in setting up electronic systems.

·         Advice on electronic systems.

·         Templates for laboratory SOPs and protocols.

·         Examples of test forms for a range of common QC microbiology tests.

·         The full range of validation documentation for laboratory equipment, from URS to IQ, OQ, and PQ files.

The various files will also be of interest to the established laboratory manager, serving as a useful best practice benchmark.

See: https://www.pharmig.org.uk/en/product/best-practices-in-microbiological-documentation-electronic-pack-one/

Setting up and Managing an Effective Training Programme in the Micro Laboratory – Electronic Pack Two

In every regulatory inspection training features and the training folder of the microbiologist is certain to be inspected. Are you using the most appropriate format for your training? This pack provides an array of templates for the full range of QC microbiology tests.

Just as important as training is assessment. But how to assess? What should be practically demonstrated? Which questions to ask of the trainee? This pack provides a range of downloadable and fully editable assessments for everything from microbial identifications to environmental monitoring.

Also included are templates to allow laboratory managers to track, trace and trend training. By purchasing this pack, the managers and the microbiology team will be audit ready.

See: https://www.pharmig.org.uk/en/product/setting-up-and-managing-an-effective-training-programme-in-the-micro-laboratory-electronic-pack-two/

LAL factsheets

Endotoxin testing is an important area for many microbiology laboratories. Training in the LAL test is often best broken down into bite-sized chunks, and these factsheets provide single-point lessons on the key aspects of the test.

Areas covered include:

·         What is LAL/BET?

·         Calculation of endotoxin limits

·         Medical devices

·         Gel clot methods

·         Photometric methods

·         Product validation quantitative methods

These areas are explained in clear and concise language, together with practical examples and with illustration.

The sheets are presented in a pack and they are laminated, making them an ideal bench-side training aid.

See: https://www.pharmig.org.uk/en/product/lal-fact-sheets/

Best practices for the Bacterial Endotoxin Test: A Guide to the LAL Assay

The core parts of the LAL test for endotoxin is described in the main pharmacopeia, but there are many things left out and others that are less clear, especially when training new staff.

This comprehensive guide describes how to:

·         How to undertake method development.

·         How to validate new samples.

·         Explains concepts like maximum Valid Dilution and Endotoxin Limits.

·         Outlines how to run a depyrogenation study.

·         Looks at medical device testing.

·         Contains a detailed trouble shooting guide.

This book provides a useful reference document for LAL users.

See: https://www.pharmig.org.uk/en/product/best-practices-for-the-bacterial-endotoxin-test-a-guide-to-the-lal-assay/

Current perspectives on Environmental Monitoring

All microbiologists need to carry out environmental monitoring, whether this is of a major plant or within the laboratory safety cabinet. Many aspects of monitoring are not well described and this Pharmig book addresses this.

The book contains chapters written by industry experts, covering:

·         How to set up an environmental monitoring programme.

·         Cleanroom microbiology.

·         How to evaluate environmental monitoring methods.

·         How to clean and disinfect effectively.

·         Tips for achieving particulate control.

·         How to run a risk assessment following an adverse trend.

Whether a beginner or an advanced practitioner, this guide has something for pharmaceutical microbiologists and their management teams.

See: https://www.pharmig.org.uk/en/product/current-perspectives-on-environmental-monitoring-review-1/

Microbiological Control for Non-Sterile Pharmaceuticals

There is far more guidance for sterile manufacturers than those involved with non-steriles in relation to microbial contamination risks and control measures. To address this gap, Pharmig has produced this guide for microbiologists working in this field.

The guide covers:

·         Best facility design requirements.

·         Microbial risks in non-sterile manufacturing.

·         Best practice tips for achieving microbial control.

·         How to clean and disinfect effectively.

·         Advice on undertaking risk assessments.

·         Microbiological testing.

·         Environmental monitoring.

The guide helps steer the microbiologists through the regulatory expectations, offering many practical examples.

See: https://www.pharmig.org.uk/en/product/microbiological-control-for-non-sterile-pharmaceuticals/

Guide to Cleanroom Operation and Contamination Control

Cleanrooms are the fabric within which most pharmaceutical processing takes place, yet not all pharmaceutical microbiologist are familiar with how they work and the contribution they make to minimising contamination.

In addition there are several different cleanroom standards and making sense of these and drawing comparisons can be changing. 

This Pharmig guide:

·         Describes the contamination control features of cleanrooms.

·         Explain the different cleanroom standards and how they compare.

·         Provides detail of the recently updated ISO 14644 standard (Parts 1 and 2).

·         Descries the different test methods for cleanrooms, like particle classification; pressure monitoring; air change rates and so on.

The guide is useful for microbiologists and cleanroom managers – helping to link engineering principles for microbiologists.

See: https://www.pharmig.org.uk/en/product/guide-to-cleanroom-operation-and-contamination-control/



Posted by Dr. Tim Sandle

Beyond Killing Tuberculosis

Historically, our view of host defense against infection was that we must eliminate pathogens to eradicate disease. However, this perspective has recently been challenged as scientists have taken a lesson from plant biologists about an ancient strategy involving the ability to “tolerate” rather than “resist” infection to maintain health. This concept, referred to as “disease tolerance”, provides an opportunity to develop new strategies that mitigate the consequences of infection.

Since the discovery of Mycobacterium tuberculosis, or Mtb, (the bacteria causing TB) over a century ago, great progress has been made in defining strategies that facilitate elimination of the bacteria. For instance, the discovery of antibiotics was a major breakthrough in the treatment of active TB. However, greater than 90 per cent of TB-infected individuals tolerate the bacteria without any treatment.

Dr. Maziar Divangahi, a pulmonary immunologist and associate director of the Translational Research in Respiratory Diseases Program at the Research Institute of the McGill University Health Centre (RI-MUHC), and a member of the McGill International TB Centre in Montreal, has been trying to explain why the vast majority of people infected with Mtb can tolerate the infection without developing disease. Clinicians refer to this condition as “latent tuberculosis”, and it affects a quarter of the global population. “TB is a perfect example of disease tolerance,” says Dr. Divangahi.

Dr. Divangahi’s team found that rather than fighting to resist the pathogen, the body’s tolerance to Mtb is the key mechanism for preventing the spread of the infection. More surprisingly, they found that having excessive levels of T cells, which are known as soldiers of our immune system, could cause more harm than good.

“We always thought that having more T cells would provide better protection against TB. Instead, we found that it could imbalance disease tolerance causing extensive tissue damage and ultimately killing the host,” says Dr. Divangahi, lead author of the study published today inScience Immunology, who is the also the associate director of the Meakins-Christie Laboratories.

Disease tolerance versus host resistance

Our body’s defense system is divided into two arms: one is resistance, which aims to eliminate the pathogen, while the other is tolerance, which is designed to control the tissue damage caused by the infection.

“While disease tolerance is an established field of research in simple organisms such as plants, our understanding of this host defense strategy in humans is very limited,” says Dr. Divangahi.

Although, immunologists and vaccinologists have made progress in the study of host resistance to infectious diseases, little is known about the mechanisms of disease tolerance in humans.

A key protein in disease tolerance

Dr. Divangahi’s team determined that a protein in the mitochondria called cyclophilin D (CypD) acts as a key checkpoint for T cell activation. Through collaboration with Dr. Russell Jones from McGill University, who is an international expert in T cell biology, they identified that CypD is required for controlling T cell metabolism. “T cells are traditionally considered to be important in eliminating Mtb,” says Dr. Divangahi. “However, we found that increasing T cell activation in mice by eliminating a metabolic checkpoint unexpectedly compromised host survival without any impact on the growth of Mtb.”

“In contrast to conventional thinking, we show that T cells are essential for regulating the body’s tolerance to Mtb infection,” explains one of the study’s first authors, Dr. Nargis Khan, who is currently a postdoctoral fellow in Dr. Divangahi’s lab at the RI-MUHC.

Giving the widespread drug resistance to various Mtb strains the limited pipeline of effective antibiotics and the lack of an efficient vaccine, alternative approaches to treat TB are urgent. “If we could understand the mechanisms of ‘natural immunity’ that controls TB in 90-95 per cent of infected individuals,” says Dr. Divangahi,“we will able to design a novel therapy or vaccine to substantially reduce the worldwide burden of this ancient disease.”
Posted by Dr. Tim Sandle

Pharmig News #71

The latest edition of Pharmig News has been issued (edition #71). In this issue:

• Update on Pharmig events
• Report from PHSS conference on Annex 1
• Pharmig’s response to the draft Annex 1
• Review of new electronic training module
• Regulatory update
• And more..

Copies have been sent to Pharmig members. If you are interested in reading a copy, contact: info@pharmig.org.uk

There are two pieces by Tim Sandle in the newsletter:

The EU GMP Annex 1 draft was subject to a consultation period during which interested partiels submitted responses. Pharmig was one of the member organisations that submitted a response. Pharmig welcomed the draft and see it as a long overdue reclarification of the requirements of sterile products manufacturing. The stronger link to Quality Risk Management and references to new technologies were particularly welcomed.

Sandle, T. (2018) Pharmig’s response to EU GMP Annex 1 draft concept paper, Pharmig News, 71, pp4-7

Pharmig has established an interactive on-line training platform. The first module covers cleaning and disinfection, aimed at GMP cleanrooms. To understand how e-learning can be delivered effectively, Tim Sandle interviewed one of the co-developers, Laura Guardi.

Sandle, T. (2018) Insight into Pharmig’s new e-learning module, Pharmig News, 71, pp7-9



Posted by Dr. Tim Sandle

ISO sanitation workshop

According to the World Health Organization (WHO), it is estimated that 2.3 billion people around the world have no access to safe, clean toilets, and where there are sanitation facilities, the waste is often not safely managed. The cost of lives is enormous, contributing to an estimated 280 000 deaths every year, not to mention the detrimental impact on people’s well-being and the environment.

News from ISO…

New technologies such as community-scaled faecal sludge treatment units, which essentially treat the waste at a community level even where there are no suitable wastewater treatment systems in place, are emerging to address this, providing a lifeline for many. Yet in order for this new technology to take off, internationally agreed guidelines are required.

As a first step, a new ISO International Workshop Agreement (IWA) has just been published, developed in partnership with the Bill & Melinda Gates Foundation and led by ANSI, ISO’s member for the USA.

IWA 28, Faecal sludge treatment units – Energy independent, prefabricated, community-scale resource-recovery units – Safety and performance, will help to facilitate the commercialization and expansion of such treatment units into the market, making them safer and more accessible to those who need them.

At the same time, a new ISO project committee – ISO/PC 318, Community scale resource oriented sanitation treatment systems – has just been formed. Bringing together international experts, it will build on the information and expertise gathered to develop IWA 28, a major step to help realize the potential of such technologies and, ultimately, save lives.

Raymond Lee, Chair of the workshop that created IWA 28, said the committee would draw on the more than 130 experts from 27 countries involved in its development to turn the IWA into a much needed International Standard.

Posted by Dr. Tim Sandle

Report on the International API inspection programme published

As part of the Certification of Suitability procedure, the EDQM runs an inspection programme for API manufacturers and is committed to optimise the inspection resources as much as possible. Therefore it has been an active member of the International API Inspection Programme since its creation back in 2008, together with the EMA, several European Union national authorities and international partners.

The report can be accessed here: EDQM

Posted by Dr. Tim Sandle

MHRA on Brexit

MHRA update to pharmaceutical companies on exit preparations. MHRA is aware that companies who market pharmaceuticals in the EU and UK will need to plan and make decisions in advance of the UK’s departure from the EU in March 2019.

The UK’s intention remains to secure an implementation period based on the existing structure of EU rules and regulations as quickly as possible, and to agree a deep and special future partnership. MHRA will continue to advise businesses on the basis of the UK position and will continue to work with the EMA in planning for the UK’s withdrawal from the EU and future relationship.

Companies have been asking for detail about UK legislative requirements in different scenarios. MHRA has been working closely with industry associations and other stakeholders and further details on all these issues and more – both Day One and longerterm proposals – will be published when appropriate.

The UK intends to agree a time-limited implementation period with the EU, and both parties have recognised its importance. Should however there be no implementation period,

MHRA’s approach would be in line with the following principles:

The European Union (Withdrawal) Bill will convert the existing EU legislative framework into UK law at the moment of exit, so there would be no sudden changes to the UK regulatory framework.

MHRA would be pragmatic in establishing UK regulatory requirements. We would give adequate notice and ensure that companies had sufficient time to implement any changed requirements.

Where possible, MHRA would be making use of the information it already has to complete administrative tasks for continuity of work and licences.

MHRA would ensure the minimum disruption and burden on companies as the UK exits the EU, while building on the existing relationship between MHRA and firms.

See: https://www.gov.uk/government/news/mhra-update-to-pharmaceutical-companies-on-exit-preparations

Posted by Dr. Tim Sandle

Guidance for pharmaceutical companies to prepare for UK’s withdrawal from EU

The European Medicines Agency (EMA) and the European Commission have updated their guidance to help pharmaceutical companies prepare for the United Kingdom’s (UK) withdrawal from the European Union (EU).

Updates to the questions-and-answers document are marked ‘NEW’ and include information on how the UK’s withdrawal will affect the status of inspection outcomes by the UK national competent authority and batch release processes for medicines that are subject to Official Control Authority Batch Release (OCABR) and Official Batch Protocol Review (OBPR). The document also clarifies how scientific opinions of the Committee for Medicinal Products for Human Use (CHMP) for ancillary medicinal substances in medical devices requested by UK notified bodies will be affected. In addition, it includes new information on back-up arrangements for Qualified Persons for Pharmacovigilance (QPPVs) and on marketing multi-country packs of medicines, where one of the countries in which the packs will be sold includes the UK.

The Agency has also published an updated version of its practical guidance for industry which outlines the steps that companies should follow to make sure that necessary changes to their marketing authorisation are made by the end of March 2019, to allow for the continued marketing of their medicine in the Union after Brexit. The document should be read in conjunction with the updated questions-and-answers document. All updates are marked ‘NEW’.

Companies are reminded to plan for the UK’s withdrawal from the EU on 29 March 2019 in order to avoid any impact on the continuous supply of medicines for human and veterinary use within the EU and are advised to regularly check EMA’s dedicated webpage on the consequences of the UK’s withdrawal from the EU.

Posted by Dr. Tim Sandle