Sunday, 31 March 2019

RSSL Introduces UK's First Same Day Mycoplasma Testing Service for Biologics

Reading Scientific Services Ltd (RSSL), a leading provider of scientific and technical solutions to the global pharmaceutical and biopharmaceutical sectors, has introduced the United Kingdom’s first same-day mycoplasma testing service for manufacturers of biologic medicines.

Traditionally, the testing required to confirm biologics are free from mycoplasma, a genus of small, hard-to-detect bacteria that lack cell walls, took 28 days and used an agar and broth method. The European Pharmacopoeia now accepts a faster, PCR-based method but other limits on turnaround times mean manufacturers still typically need to wait two or more days to receive results.

RSSL has used its established processes for sample handling and tracking to eliminate the constraints that have kept turnaround times above 48 hours. If a manufacturer gets a sample to RSSL by 9:30am, it will receive mycoplasma testing results by 5pm.

RSSL has reduced the time it takes to execute this process to serve the UK’s fast-growing advanced therapy medicinal products (ATMPs) sector. Production of ATMPs such as autologous cell and gene therapies entails taking a sample from a patient, processing it and re-administering it back into the same patient within 15 days, making speed a priority.

The highly trained and professional team at RSSL initially use automated technology to extract DNA for testing, followed by real-time PCR for mycoplasma using regulator-accepted commercial analysis kits such as the Roche MycoTOOL Mycoplasma Real-Time PCR Kit. RSSL is offering clients a choice of Real-Time PCR based kits based on their individual requirements.

Multiple sample types can be used for the analysis although spent culture media is preferred, as this is easily available and will contain any mycoplasma that may have contaminated the process. Some preliminary sample validation is still required to ensure there are no components within the test material that will interfere with the PCR technique.

“Speed of service is critical to manufacturers of autologous cell and gene therapies. These companies have a window of 10 to 15 days to execute the entire supply chain and manufacturing process. They simply don’t have time to wait for traditional mycoplasma testing methods,” Phil Kuhlman, Biomolecular Analysis Laboratory Manager at RSSL, said.

RSSL offers longer turnaround times that may be more suitable for producers of traditional biologics but, with the UK emerging as a leader in ATMPs, it saw an unmet need for a one-day service. With 64 developers of ATMPs, the UK has more companies in the sector than any other European country.1 The manufacturing capacity in place to serve these companies increased by 60% in the year preceding November 20182.

RSSL, which collaborates closely with commercial kit suppliers, offers the mycoplasma testing service as part of a broader suite of ATMP support. ATMP companies rely on RSSL for tests of raw materials, process and product related impurities , host cell protein and DNA and pharmaceutical microbiology . RSSL also provides GMP training , product issue troubleshooting and contaminant identification .

Whatever your testing requirements, contact the RSSL customer services team to discuss your requirements further on +44 (0)118 918 4076 or email

Posted by Pharmaceutical Microbiology

FDA guidance: Labeling for human prescription drug under accelerated approval regulatory pathway

New FDA guidance, which is intended to assist applicants in developing the INDICATIONS AND USAGE section of labeling for human prescription drug and biological products has been issued.
This is for drugs that are approved under the accelerated approval regulatory pathway (hereafter accelerated approval) as defined in section 506(c) of the Federal Food, Drug, and Cosmetic Act (FD&C Act) and 21 CFR part 314, subpart H, or 21 CFR part 601, subpart E. More specifically, this guidance focuses on indications for drugs approved via accelerated approval on the basis of a surrogate endpoint or a clinical endpoint other than survival or irreversible morbidity. This guidance also addresses labeling considerations for indications that were approved under accelerated approval and for which clinical benefit subsequently has been verified and the FDA terminates the conditions of accelerated approval under 21 CFR 314.560 or 21 CFR 601.46. In addition, this guidance addresses labeling considerations when the FDA withdraws approval of an indication that had been approved through the accelerated approval pathway while other indications for the drug remain approved.


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Saturday, 30 March 2019

WHO guidance on testing of “suspect” falsified medicines

This new World Health Organization document provides technical guidance on laboratory testing of samples of suspect deliberately falsified medical products detected on the markets of WHO Member States and related aspects of sampling and reporting. This guidance should be read in conjunction with the guidelines on sampling and market surveillance.

“Suspect” medicines can be divided into three main categories of products as follows:

(a) substandard medicines - Also called “out of specification”, these are authorized medicines that fail to meet either their quality standards or their specifications, or both.

(b) unregistered/unlicensed medicines - Medicines that have not undergone evaluation and/or approval by the national regulatory authority (NRA) for the market in which they are marketed/distributed or used, subject to permitted conditions under national or regional regulation and legislation. These medicines may or may not have obtained the relevant authorization from the NRA of their geographical origin.

(c) falsified medicines - Medicines that deliberately/fraudulently misrepresent their identity, composition or source. Any consideration related to intellectual property rights does not fall within this definition. Such deliberate/fraudulent misrepresentation refers to any substitution, adulteration, reproduction of an authorized medicine or the manufacture of a medicine that is not an authorized product.

Within the document it defines falsified medicines as medicines that deliberately/fraudulently misrepresent their identity, composition or source. Any consideration related to intellectual property rights does not fall within this definition. Such deliberate/fraudulent misrepresentation refers to any substitution, adulteration, reproduction of an authorized medicine or the manufacture of a medicine that is not an authorized product.

This document provides technical guidance on laboratory testing of samples of suspect deliberately falsified medical products detected on the markets of WHO Member States and related aspects of sampling and reporting. This guidance should be read in conjunction with the guidelines on sampling and market surveillance. Within the document it defines falsified medicines as medicines that deliberately/fraudulently misrepresent their identity, composition or source. Any consideration related to intellectual property rights does not fall within this definition. Such deliberate/fraudulent misrepresentation refers to any substitution, adulteration, reproduction of an authorized medicine or the manufacture of a medicine that is not an authorized product.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Friday, 29 March 2019

How a fungus can cripple the immune system

The fungus Aspergillus fumigatus occurs virtually everywhere on Earth, as a dark grey, wrinkled cushion on damp walls or in microscopically small spores that blow through the air and cling to wallpaper, mattresses and floors. Healthy people usually have no problem if spores find their way into their body, as their immune defence system will put the spores out of action. However, the fungus can threaten the lives of people with a compromised immune system, such as AIDS patients or people who are immunosuppressed following an organ transplantation.

An international research team led by Prof. Oliver Werz of Friedrich Schiller University, Jena, has now discovered how the fungus knocks out the immune defences, enabling a potentially fatal fungal infection to develop. Among other factors, it is gliotoxin -- a potent mycotoxin -- that is responsible for the pathogenicity of Aspergillus fumigatus. "It was known," says study manager Werz of the Institute of Pharmacy at the University of Jena, "that this substance has an immunosuppressive effect, which means that it weakens the activity of cells of the immune defence system." However, it had not been clear previously how exactly this happens. Werz and his team colleagues have now studied this in detail and have clarified the underlying molecular mechanisms.

To achieve this, the researchers brought immune cells into contact with synthetically produced gliotoxin. These cells, called neutrophilic granulocytes, represent the first line of the immune defence system.

See: Gliotoxin from Aspergillus fumigatus Abrogates Leukotriene B4 Formation through Inhibition of Leukotriene A4 Hydrolase. Cell Chemical Biology
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Thursday, 28 March 2019

Human gut bacterium reveals possible connection to depression

Research team studies the compelling connection between one of NIH's "most wanted" bacteria and mental health. Scientists have established a correlation between depression and a group of neurotransmitter-producing bacteria found in the human gut.

The research team from the U.S. Department of Energy's (DOE) Argonne National Laboratory, Northeastern University and elsewhere made the connection by first isolating the KLE1738, a bacterium that has a surprising dependency upon a brain chemical called gamma-aminobutyric acid (GABA).

The general ability of the microbiome to produce and/or consume GABA has not been as broadly described before, and a bacterium dependent on GABAhas never been reported. KLE1738 had previously appeared on the "most wanted list" of the National Institutes of Health, meaning that it had yet to be cultured, despite its relative prevalence in the human gut. The bacterium has been detected in nearly 20 percent of the human gut microbiomes available in the Integrated Microbial Next Generation Sequencing Database.

Gut microbiota, the entire collection of microorganisms found in that habitat, affect many important functions, including the immune response and the nervous system. Nevertheless, many microorganisims residing in the human gut remain uncultured, which the research team called "an obstacle for understanding their biological roles" in the Nature Microbiology article.

More such microorganisms probably remain uncultured because they require key growth factors that are provided by neighboring bacteria in their natural environments, but not under artificial laboratory conditions. During an extensive screening process, the team found that KLE1738 required the presence of Bacteroides fragilis, a common human gut bacterium, to grow.

Further biological testing and purification led to the isolation of GABA as the growth factor produced by Bacteroides fragilis. GABA was, in fact, the only nutrient tested during the experiments that supported the growth of KLE1738.

In the next research phase, the team explored the possible connection between Bacteroides and depression. Stool samples and functional magnetic resonance imaging measurements of brain activity were collected from 23 subjects suffering from clinically diagnosed depression.

The researchers found an inverse relationship between the relative abundance of fecal Bacteroides and functional connectivity in a part of the brain associated with elevated activity during depression. This means that low abundance of Bacteroides was associated with high activity in that part of the brain, and vice versa.

See: GABA-modulating bacteria of the human gut microbiota. Nature Microbiology

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Wednesday, 27 March 2019

Global approach to development of new antibacterial medicines

Antimicrobial resistance is a global public health problem. Regulators in the EU, the USA and Japan have had extensive discussions over the last few years to explore and agree how to align as much as possible their respective data requirements so that medicine developers can design clinical trials that meet the evidence needs of multiple regulatory agencies. The revised guidance reflects the outcome of these discussions. In addition, it offers clarification on the clinical development of antibacterial agents that are expected to address an unmet medical need, in accordance with experience.

The emerging and steady increase of microbes that are resistant to antimicrobial treatments has become a global public health concern that threatens the effective treatment of infectious diseases. Combatting this threat, particularly resistance to antibiotics, is a high priority for the European Medicines Agency (EMA) and the European medicines regulatory network.
Antimicrobial resistance is when a microbe evolves to become more or fully resistant to antimicrobials which previously could treat it. Antimicrobials include antibiotics, which kill or inhibit the growth of bacteria.

A well-known example of a bacterium that is resistant to a number of antibiotics is meticillin-resistant Staphylococcus aureus (MRSA), which has caused infections that are difficult to treat across the European Union (EU).

The emerging and steady increase in the occurrence of bacteria that are resistant to multiple antibiotics has become a global public health threat due to the lack of therapeutic options to treat certain infections in humans.

Specific advice has also been added with regards to the EU regulatory requirements to develop medicines for the treatment of uncomplicated urinary tract infections and gonorrhoea. The draft revised guideline was adopted by EMA’s human medicines committee (CHMP).


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Tuesday, 26 March 2019

FDA: Immunogenicity Testing of therapeutic protein products

FDA have issued a new draft guidance for developing and validating assays for anti-drug antibody detection.

This guidance provides recommendations to facilitate industry’s development and validation of assays for assessment of the immunogenicity of therapeutic protein products during clinical trials. Specifically, this document includes guidance regarding the development and validation of screening assays, confirmatory assays, titration assays, and neutralization assays. For the purposes of this guidance, immunogenicity is defined as the propensity of a therapeutic protein product to generate immune responses to itself and to related proteins or to induce immunologically related adverse clinical events. The recommendations for assay development and validation provided in this document apply to assays for the detection of one or more anti- drug antibodies (ADAs). This guidance may also apply to some peptides, oligonucleotides, and combination products on a case-by-case basis. 


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

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 Saarbr├╝cken (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

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