Book review: Pharmaceutical Regulatory Inspections

Pharmaceutical Regulatory Inspections  - Reviewed By Victor Grayson, Sterile Operations Manager, BPL (Pharmig News Number 60, p12)

Understanding the international regulatory field is an area of growing complexity and pharmaceutical facilities frequently face inspections from different global inspectorates, as well as their own national bodies. Keeping up with current Good Manufacturing Practices (GMP) can often be challenging.

To help with this complex task a new book has been produced “Pharmaceutical Regulatory Inspections”, edited by Madhu Raju Saghee. The book is timely, relevant and important.

The book contains chapters written by a number of international experts and covers everything anyone could possibly wish to know about the inspection process and quality issues affecting pharmaceuticals and healthcare.

In order to establish a baseline, the book opens with a very useful chapter by Tim Sandle and Madhu Raju Saghee which explores basic concepts of GMP and address global differences. The book then moves onto cover some key and specific topic areas including the FDA approach to GMP inspections; the current paradigm of ‘system based’ inspections and pre-approval inspections.

The book not only explains the inspection process, it also covers the key points that are likely to arise during an inspection or audit. This includes documentation, electronic systems, staff training, hygiene, licencing, compliance and so forth. The quality of the explanations is high and the book is packed full of useful examples and case studies.

Among the latter chapters of high quality is one by Siegfried Schmitt and Nabila Nazir which looks at the European inspection approach, breaking down the complexity of European regulations into a digestible format. Another useful chapter is where Tim Sandle, Madhu Raju Saghee and David Barr outline a strategy whereby organisations can respond to inspection observations in a timely, sensible and risk centric way.

For this reviewer the two gems of the book are the two closing chapters. One by Siegfried Schmitt and Richard Einig provides a survival guide for surviving inspections of API facilities; and another by Tim Sandle provides the most comprehensive guide for dealing with inspections of sterile facilities that this reviewer has ever come across.

In summary, this is an important book and it is an unique book. It is an essential item for the book shelf of anyone involved with quality inspections, audits or GMP.

Pharmaceutical Regulatory Inspections can be obtained from the publisher, Euromed

FDA Tackles Broken Generic Drug Application Process

“Today nearly 84 percent of all prescriptions filled in the U.S. are generic. The generic industry’s trade group, the Generic Pharmaceutical Association (GPhA), has released figures that show the impact of generic drugs: over the last 10 years, generic drugs have saved consumers in excess of 1.2 trillion dollars. At the same time, the FDA has been making steady progress in narrowing the gap between brand drugs and generic drugs in terms of quality and efficacy.”

This is the interesting opening part of an article by Bikash Chatterjee for Controlled Environments. The full article can be accessedhere.

Posted by Tim Sandle

Mechanism of action of amphotericin

Researchers now understand the mechanism of action of amphotericin, an antifungal drug that has been in use for more than 50 years -- even though it is nearly as toxic to human cells as it is to the microbes it attacks.

Studies have found evidence that amphotericin opens up ion channels in membranes, perhaps making them leakier to charged atoms that could disrupt a cell. Most scientists assumed that this was the drug's main mode of action. But the evidence also suggested that amphotericin interacted with sterols, such as cholesterol in animal cells and ergosterol in yeast. Rienstra and Burke focused on amphotericin's influence on sterols, hypothesizing that this might be a key to its toxicity.

The initial data supported this idea, indicating that very little of the drug -- less than 5 percent -- actually formed channels in membranes. Using nuclear magnetic resonance and other experimental tools, a research team have found that most of the amphotericin aggregates on the exterior of membranes, extracting sterols out of membranes like a sponge. Cell death follows soon after.

The research was carried out at Chad Rienstra. A report of the new findings has been published in Nature Chemical Biology:

Thomas M Anderson, Mary C Clay, Alexander G Cioffi, Katrina A Diaz, Grant S Hisao, Marcus D Tuttle, Andrew J Nieuwkoop, Gemma Comellas, Nashrah Maryum, Shu Wang, Brice E Uno, Erin L Wildeman, Tamir Gonen, Chad M Rienstra, Martin D Burke. Amphotericin forms an extramembranous and fungicidal sterol sponge. Nature Chemical Biology, 2014; DOI: 10.1038/nchembio.1496

Posted by Tim Sandle

Monitoring cleanrooms using a rapid micro method

A new paper of interest has been published.

In the paper, the researchers assessed the different operational states within a biopharmaceutical grade clean room, using a rapid microbiological method. The method was a novel system, based on spectrometry, designed for sampling, discriminating, and enumerating airborne particles (a BioVigilant IMD-A® System).

Central to the study was the aim to determine the microbiological levels as a clean room went from standard use through maintenance and shutdown, disinfection, and then back to standard use. The objective was to evaluate whether a rapid method could replace conventional environmental monitoring using growth-based media.

The paper concludes that the optical instrument can be used to process sufficient information, so that clean rooms can be returned to use following a period of unexpected downtime or following maintenance without the need to wait for the results from growth-based methods. As such, this type of rapid microbiological method is worth exploring further for clean room air monitoring.

The reference is:

Sandle, T., Leavy, C., Jindal, H. and Rhodes, R. (2014) Application of rapid microbiological methods for the risk assessment of controlled biopharmaceutical environments, Journal of Applied Microbiology, 116 (6): 1495-1505

Posted by Tim Sandle

Directory of Community Blood Centers and Hospital Blood Banks

Directory of Community Blood Centers and Hospital Blood Banks, 5th edition contains profiles of facilities from around the world. Details on volume and types of components collected, outdate rates, computer systems, governance, contact personnel and many more aspects of operations at each participating facility make this an invaluable resource.

Those involved in blood baking can compare their facility's performance with that of other institutions, network with colleagues about infrequently encountered procedures, locate where special services are offered, and find other key information to help their institution run efficiently. In addition to the facility descriptions, this volume contains listings of immunohematology reference laboratories and marrow donor centers, information on using the National Blood Exchange, and a handy chart that cross-references special services.

For further details see: Blood Bank

Posted by Tim Sandle

Predicting MRSA Toxicity

A comparative genomic study shows that researchers can use genetic signatures to predict the toxicity of methicillin-resistant Staphylococcus aureus isolates.

An international team led by Ruth Massey at the University of Bath in the U.K. reported a comparative genomic study of 90 methicillin-resistant Staphylococcus aureus (MRSA) strains in Genome Research. Analyzing genome-wide data, Massey and her colleagues were able to predict the toxicity of any given isolate based on genetic signatures. The researchers proposed that their approach could inform similar strategies to better understand other drug-resistant pathogens.







Posted by Tim Sandle

Flow Cytometry handbook (free)

Flow cytometry is a laser-based, biophysical technology employed in cell counting, cell sorting, biomarker detection and protein engineering, by suspending cells in a stream of fluid and passing them by an electronic detection apparatus. It allows simultaneous multiparametric analysis of the physical and chemical characteristics of up to thousands of particles per second.

Flow cytometry is routinely used in the diagnosis of health disorders, especially blood cancers, but has many other applications in basic research, clinical practice and clinical trials.

AbD Serotec are offering a free e-book. The book contains an overview of the principles of light and flow cytometry, basic data analysis and common protocols. It is perfect for students or inexperienced users of this powerful application.

For details see Flow Cytometry

Posted by Tim Sandle

Environmental monitoring webinar

A recorded webinar on environmental monitoring and an innovative new design of agar plate is available to view on the Cleanroom Technology website. The webinar is free to view.

The description of the webinar is:

“With the help of Thermo Scientific™ Triple Wrapped Irradiated Plates, industry leaders John Cobb and Colin Booth will walk viewers through qualification test protocols, guidelines and technical tips needed to successfully reduce the risk of contamination in cleanrooms and isolators. It’s all about giving you the cleanroom confidence you need to succeed.”

To view the webinar, visit CleanroomTechnology.

Posted by Tim Sandle

A Role for Endotoxin in Clinical Depression

Chronic activation of the inflammatory response plays a role in clinical depression.  This inflammation is associated with increases in endotoxin-specific IgA, indicating that bacterial translocation is significant.  An international group of scientists led by the Polish Academy of Science used this observation to develop an animal model for depression using endotoxin injections.  With this model they were able to demonstrate a reversal of endotoxin-induced effects with an antidepressant.  This work, published in the journal Brain, Behavior, and Immunity, underscores the importance of endotoxin in neurobehavioral conditions.

Refer to the following paper:

"A new animal model of (chronic) depression induced by repeated and intermittent lipopolysaccharide administration for 4 months."

Scientists at BioDtech, Inc. have measured previously undetectable levels of endotoxin which could cause activation of the immune system.  BioDtech products are designed to more accurately detect endotoxin and remove it from proteins and DNA.

Posted by Tim Sandle

Review of cleanliness services in hospitals

A draft standard of interest has been published for public comment. It is coded PAS 5748:2014 and titled “Specification for the planning, application, measurement and review of cleanliness services in hospitals”.

It specifies requirements for:

a) governing cleanliness services;

b) assessing risk and categorizing elements and functional areas;

c) providing cleaning tasks, including:

1) identifying cleaning tasks;

2) risk assessment of cleaning tasks;

3) providing method statements;

4) setting cleaning frequencies;

5) setting work schedules;

6) establishing competence;

7) contingency planning;

d) measuring cleanliness on the basis of visual assessment;

e) implementing corrective action;

f) conducting performance analysis and implementing improvement actions;

g) providing a continuous service improvement plan; and

h) reporting cleanliness.

In the draft standard, two types of risk are specifically identified:

infection risk – The risk of infection for patients; and

confidence risk – The risk of a poor public image and the loss of confidence in patients and staff of the organization’s ability to provide a clean, safe environment for care.

To review the standard, please contact your national standards office.

Posted by Tim Sandle

Food-Poisoning Microorganisms

Identification methods can be divided into two groups: phenotypic and genotypic. The genotype–phenotype distinction is drawn in genetics. ‘Genotype’ is an organism’s full hereditary information, even if not expressed. ‘Phenotype’ is an organism’s actual observed properties, such as morphology, development, or behaviour.

This is the introduction to a chapter by Tim Sandle for the new edition of the Encyclopedia of Food Microbiology. The reference is:

Sandle, T., 2014. Biochemical and Modern Identification Techniques: Food-Poisoning Microorganisms. In: Batt, C.A., Tortorello, M.L. (Eds.), Encyclopedia of Food Microbiology, 2^nd edition, vol 1. Elsevier Ltd, Academic Press, pp. 238–243

Written by the world's leading scientists and spanning over 400 articles in three volumes, the Encyclopedia of Food Microbiology, Second Edition is a complete, highly structured guide to current knowledge in the field. Fully revised and updated, this encyclopedia reflects the key advances in the field since the first edition was published in 1999

The articles in this key work, heavily illustrated and fully revised since the first edition in 1999, highlight advances in areas such as genomics and food safety to bring users up-to-date on microorganisms in foods. Topics such as DNA sequencing and E. coli are particularly well covered.

With lists of further reading to help users explore topics in depth, this resource will enrich scientists at every level in academia and industry, providing fundamental information as well as explaining state-of-the-art scientific discoveries.

For details see: Encyclopedia of FoodMicrobiology

To review a copy, please contact Tim Sandle.

Posted by Tim Sandle

Free e-book: How to accelerate early clinical development

Terrapinn have issued a free e-book about clinical development. According to the company:  “In this ebook, we share the thoughts of early clinical development leaders on the challenges, approaches and changes affecting early clinical development.”

The book features:

• Sif Ormarsdottir, MD, PhD, Specialist Gastroenterology and Hepatology, Chair, Hepatotoxicity Safety Knowledge Group, AstraZeneca Ab
• Mikko Kuoppamaki, MD, PhD, Head of Medical Affairs Team, Research & Development, Orion Pharma
• Marek Honczarenko, MD, PhD, Group Medical Director Immunoscience, Exploratory Clinical & Translational Research, Bristol-Myers Squibb

These leaders in clinical research and development will be speaking at Exploratory Clinical Development World Europe this 3-5 June in London. 

For details about the book, see: Health Network

Posted by Tim Sandle

The influence of the gut microbiota on neurology

Can gut microbes manipulate even the mind? New research seems to suggest that the answer is yes.

A mouse study of autism spectrum disorders showed an association between changes in the gut microbiota and ASD symptoms. These findings could indicate that the microbiota have a significant impact on the perturbations associated with neurodevelopmental disorders.

(2013, Cell 155, 1451).

Posted by Tim Sandle

Method offers potential for understanding anti-bacterial resistance

By basing methods on mathematical models and Bayesian analysis, the researchers have succeeded in producing tools for biologists who are interested in jumping genes and the traits they carry with them. This could provide a deeper understanding about how species have evolved, and even find ways to address antibiotic resistance.

The method and model could be used in order to see the kinship between species more clearly than before. The method describes an algorithm and associated software, which will be an important tool for researchers working with bacteria and the genes they transmit laterally, such as for antibiotic resistance.

For further details, see:

J. Sjostrand, A. Tofigh, V. Daubin, L. Arvestad, B. Sennblad, J. Lagergren. A Bayesian Method for Analyzing Lateral Gene Transfer. Systematic Biology, 2014; DOI: 10.1093/sysbio/syu007

Posted by Tim Sandle

Sharpening microscope images

Biological samples bend light in unpredictable ways, returning difficult-to-interpret information to the microscope and distorting the resulting image. To overcome this, new imaging technology developed at the Howard Hughes Medical Institute's Janelia Farm Research Campus rapidly corrects for these distortions and sharpens high-resolution images over large volumes of tissue.

To improve the method, researchers focused on devising an adaptive optics strategy for new microscopy methods that image dynamic processes non-invasively and at high resolution. Such technologies -- such as the Bessel beam plane illumination microscope that Betzig's team developed in 2011 and the simultaneous multiview light sheet microscope developed by Janelia lab head Philipp Keller in 2012 -- perform well on cells or small embryos, but image quality degrades in larger samples.

Those microscopes are used exclusively to image transparent samples, narrowing the scope of the problem.

For further information, refer to:

Kai Wang, Daniel E Milkie, Ankur Saxena, Peter Engerer, Thomas Misgeld, Marianne E Bronner, Jeff Mumm, Eric Betzig. Rapid adaptive optical recovery of optimal resolution over large volumes. Nature Methods, 2014; DOI: 10.1038/nmeth.2925

Posted by Tim Sandle