PHSS Annual Members Conference 2014

Processing challenging Pharmaceutical, Biopharmaceutical and Therapy products to GMP: Managing compliance, control, monitoring and efficiency challenges.

A new conference on interest is taking place  in London on September 12, 2014.

As new Biological products, challenging toxic products and Cellular / Gene therapies (ATMPs) are developed there are increasing challenges in GMP compliance. With more complex products that have increased efficacy and efficiency in targeted delivery systems the challenges in processing and GMP compliance with a focus on patient safety require new strategies, technologies and practice.

The regulatory, product and processing environments are changing and it is important to keep up with these trends.

Today we have to balance the use of Closed and Open system processing technologies, technique and practice to manage risks and interfaces processing large and small batches and for therapies essentially ‘one product, one batch, one patient’.

There is a need to think more strategically on how to approach processing of such products to manage quality, safety, efficacy and patient safety with GMP compliance.

This conference considers the challenges to address, strategies, new technologies and practice developing to meet the new challenges…..not one to miss.

• Attendance is free to all PHSS Members.
• Non-members can simply join the PHSS (£90 + vat) so the conference and 12 months membership in one.

The PHSS Bio-contamination monograph will be released at this conference.

For details see: PHSS brochure

Posted by Tim Sandle

FDA: Endotoxin Testing for Single-Use Intraocular Ophthalmic Devices

A new FDA guidance document has been developed to notify manufacturers of the recommended endotoxin limit for the release of intraocular devices and single-use intraocular ophthalmic surgical instruments/accessories in an effort to mitigate future Toxic Anterior Segment Syndrome (TASS) outbreaks.

TASS is a sterile inflammatory condition localized to the anterior segment of the eye following intraocular surgery. It has been associated with significant decreases in vision and has required additional surgical procedures, including corneal transplants and glaucoma surgery, to resolve some of its sequelae.

National outbreaks of TASS have been associated with endotoxin. Devices used inside the eye, including intraocular devices and single-use intraocular ophthalmic surgical instruments/accessories, can potentially be contaminated with endotoxin as part of the manufacturing, sterilization, or packaging processes. This guidance document provides recommendations for endotoxin limits as well as endotoxin testing to manufacturers and other entities involved in submitting premarket applications (PMAs) or premarket notification submissions [510(k)s] for different categories of intraocular devices to aid in the prevention of future outbreaks of TASS.

For details of the draft, see FDA

Posted by Tim Sandle

Inter-governmental Working Meeting on Pharmacy Compounding

The U.S. Food and Drug Administration (FDA) convened an inter-governmental working meeting of state government officials, including officials from the District of Columbia and Puerto Rico. During this meeting, participants discussed oversight of compounding pharmacies and implementation of the Drug Quality and Security Act (DQSA).

The DQSA, P.L. 113-54, was signed into law on November 27, 2013, and contains provisions relating to federal and state oversight of compounded human drugs. The purpose of this meeting was to identify opportunities to better protect the public health by strengthening oversight of compounders, including through improved federal-state collaboration.

For more details, see FDA

Posted by Tim Sandle

Good Distribution Practice for Medicinal Products for human use

The European Commission has issued an updated to questions and answers relating to Good Distribution Practice (GDP).  Q&A has been updated in order to clarify the EU GDP guideline.

There are 25 questions and answers within the document.

For example:

QUESTION: In Chapter 3 – Premises and Equipment, 3.2.(3), is the intent of segregation to avoid ‘cross contamination’ as mentioned in Chapter 5?

Answer: The intent of this provision is to avoid handling errors and accidental swaps of products. This is why electronic segregation is allowed, except for falsified, expired, recalled and rejected products which always have to be segregated physically.

To view the document, go to EU GDP.

Posted by Tim Sandle

How to create a hygienic work environment

Maintaining a hygienic work environment is especially important in certain sectors, such as healthcare and catering. However, all workplaces should be kept clean. After all, failing to create hygienic conditions can lead to a range of ill-effects. For example, it can cause sickness rates to increase among employees, which is bad news for companies’ bottom lines. It can also lower morale levels. No one wants to work in unclean conditions.

To help ensure your workplace is spic and span, you can follow the advice provided in this simple hygiene guide.

Basic housekeeping

First and foremost, it’s vital that you engage in good basic housekeeping. For example, your workspace should be vacuumed, swept or mopped on a regular basis to get rid of dust and dirt. Also, all work surfaces including desks should be wiped with suitable cleaning products. In addition, it is important to clean computer equipment and phones as these items are particularly likely to accumulate germs.

Food preparation areas including kitchens and break areas must be kept clean at all times too.

Washroom sanitation

Of course, it’s no good going to great lengths to keep your working area clean if you then fail to provide suitable washroom sanitation. All toilet areas should be well stocked with toilet roll and soaps. These spaces should also be thoroughly disinfected on a frequent basis.

Encouraging good practices

Your personnel may not spend much time thinking about workplace hygiene, especially if you rely on a cleaning firm to keep your premises in good order. However, it is important to let your staff members know that they have their own roles to play in minimising germs.

For example, remind them of the importance of keeping their workstations clean and try to discourage them from eating at their desks. No matter how careful they are, people are bound to create some level of mess when they consume food in front of their computer screens and this can cause bacterial levels to build up.

Also, it’s a good idea to put signs up in your toilets to help ensure that people always wash their hands.

Disposing of rubbish

Another important area of hygiene control concerns waste disposal. It’s crucial that you have an effective system in place for getting rid of rubbish. For example, any food waste much be disposed of quickly before it can present a risk to health.

The right tools for the job

To follow these basic principles, you’ll need to have access to all the relevant tools and resources, including suitable cleaning chemicals, bins, soap dispensers, toilet roll holders and so on.

Luckily, it’s now simple to purchase items like these. Companies such as Brammer offer a full range of industrial cleaning and janitorial products and should have everything you need.

Keeping on top of hygiene does require some effort and expenditure, but this is a worthwhile investment. It can help to keep your personnel healthy and happy, and it can make your environment a more pleasant place in which to spend time.

Posted by Tim Sandle

EU GMP Chapter 6: Quality Control

The new version of chapter 6 of the EU GMP Guide comes into effect on 1^st October 2014.

“Quality Control is concerned with sampling, specifications and testing as well as the organisation, documentation and release procedures which ensure that the necessary and relevant tests are carried out, and that materials are not released for use, nor products released for sale or supply, until their quality has been judged satisfactory. Quality Control is not confined to laboratory operations, but must be involved in all decisions which may concern the quality of the product. The independence of Quality Control from Production is considered fundamental to the satisfactory operation of Quality Control.”

The final version includes of a new section on technical transfer of testing methods and other items such as Out Of Specification results. There is also a new section on the technical transfer of analytical methods.

To view the final version, see Eudralex

Posted by Tim Sandle

Anthrax: History, Biology, Global Distribution, Clinical Aspects, Immunology, and Molecular Biology

Following the post 9/11 distribution of anthrax spores through the U.S. mail, and the resulting deaths of five individuals - primarily due to initial misdiagnosis - there has been a renewed interest in anthrax among clinicians and intelligence agencies, particularly as a biological warfare agent. This monograph brings forth essential knowledge about anthrax. Included in this volume, are, the early history, non-natural outbreaks of anthrax, characteristics of the causative organism Bacillus anthracis and its relationship to other members of the B. cereus family. Also included are reports on extensive clinical findings, mechanisms of anthrax virulence and the genetics responsible for these virulence factors. The extensive studies over the years regarding the development of veterinary and human vaccines, and molecular studies, including conventional PCR and real-time PCR are explained in comprehensive detail, with the help of tables, figures and extensive references.  This eBook serves as an advanced presentation and reference work for individuals seeking detailed information regarding anthrax and as a primary guide for individuals pursuing studies on anthrax.

A new e-book of interest has been published. The chapter details are:

1. History, Global Distribution, and Non-Natural Incidents of Anthrax

2. Characteristics of Bacillus anthracis

3. Clinical Aspects and The Infectious Process of Anthrax

4. Functionality of Bacillus anthracis Toxins

5. Vaccine Development and Immunological Aspects of Bacillus anthracis

6. Genetics and Molecular Techniques for Detection and Identification of Bacillus anthracis

 For further details see: Anthrax book

Posted by Tim Sandle

U.S. CDC - influenza vaccine for this coming autumn.

The 2013–14 influenza season began early, was pH1N1 predominant, and was relatively more severe than recent influenza seasons for adults aged less than 65 years. This season is a reminder that influenza viruses can affect all ages and that yearly vaccination is the best step to take to prevent illness from influenza and its associated complications. The 2013-14 influenza season was the first Influenza A (H1N1) pdm09 (pH1N1) predominant season since the 2009 pandemic. It was characterized by lower overall levels of outpatient illness and mortality than influenza A (H3N2)–predominant seasons, but higher rates of hospitalization among adults aged 18–64 years compared to recent years. Although influenza activity is typically low in the summer, cases of influenza and even influenza outbreaks occur in the United States throughout the summer. Healthcare providers should remain vigilant and consider influenza as a potential cause of summer respiratory illnesses, and should consider treatment with influenza antiviral medications for those at high risk for influenza-associated complications

Posted by Tim Sandle

Enterobacteriaceae, Coliforms, and Escherichia Coli

The Enterobacteriaceae is a large family of Gram-negative bacteria that includes, along with many harmless symbionts, many of the more familiar pathogens, such as Salmonella, Escherichia coli, Yersinia pestis, Klebsiella, Shigella, Proteus, Enterobacter, Serratia, and Citrobacter. Members of the Enterobacteriaceae are rod shaped and typically are 1–5 mm in length. Enterobacteria have Gram-negative stains, and they are facultative anaerobes, fermenting sugars to produce lactic acid and various other end products. Many members of this family are a normal part of the gut flora found in the intestines of humans and other animals, whereas others are found in water or soil, or are parasites on a variety of different animals and plants.

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: Enterobacteriaceae, Coliforms, and Escherichia Coli. In: Batt, C.A., Tortorello, M.L. (Eds.), Encyclopedia of Food Microbiology, 2^nd edition, vol 1. Elsevier Ltd, Academic Press, pp. 232–237

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 Food Microbiology

To review a copy, please contact Tim Sandle.

Posted by Tim Sandle

Malnutrition Affects the Microbiome

The gut bacterial communities of severely malnourished children appear to be less developed than those of healthy children, a study on Bangladeshi infants and toddlers finds.

The gut microbiomes of young children do not fully recover from the trauma of early-life malnourishment, even after they are treated with more-complete diets, according to a study published in Nature.

A team led byJeffrey Gordon of the Washington University in St. Louis sampled the gut microbiomes of healthy and malnourished children in Bangladesh and found that the microbiomes of children who were underfed and whose diets lacked essential nutrients looked less like those of adults and more like those of younger, healthy children.

The findings present a possible explanation for the commonly observed complications that malnourished children suffer even after they are treated with a standardized food regimen, including stunted growth, cognitive delays, and immune system problems. The researchers suggested that the immature gut microbiomes of malnourished children may be partially responsible for some of these long-term impairments.

The researchers collected monthly fecal samples from a dozen healthy children in Mirpur—an impoverished region in the city of Dhaka—for the first two years of their lives. By the time they are toddlers, most children develop gut microbiomes that are similar to those of adults. The researchers used 16S ribosomal sequencing to identify bacterial taxa in the children’s fecal samples, narrowed the results down to 24 key taxa, and created a mathematical model to analyze the data.

They then applied that model to 38 other healthy children and used the results to develop two measurement tools, which the researchers labeled “relative microbiota maturity” and “microbiota-for-age Z-score."

The researchers used these measurements to refine the model, and then applied the model to study the microbiomes of 64 severely malnourished children before, during, and after they were assigned to one of two diets meant to treat malnutrition. The first was a standardized, ready-to-use therapeutic food called Plumpy’nut—a peanut-based treatment for malnutrition that is widely used by non-governmental organizations around the world. The other diet consisted of low-cost, locally produced calorie-rich foods, khichuri and halwa. Children in both treatment groups gained the same amount of weight post-treatment, but they remained underweight and fell short of typical height measurements.

The team found that before and immediately after treatment, the gut microbiomes of children in both malnourished groups were immature compared to healthy controls. After a month, the children’s microbiomes improved dramatically, but that improvement did not last for more than a few months. At four months, the microbiomes of both malnourished groups appeared to regress to a less-mature state, and the microbes in their guts were less diverse than were those collected from healthy children.

The findings show “a persistent delay in maturation of this organ in malnourished children,” Gordon said. “If we are to repair the dysfunction associated with malnutrition, we’re going to have to look not only to our human cellular parts, but also to our microbial parts.”

The researchers repeated the experiment in a group of healthy children from Malawi and found a similar maturation and shift in gut microbes as the children grew older. However, Neu noted, the findings of the current study are not yet generalizable to populations in other parts of the world. But he believes the technique that Gordon, Subramanian, and their colleagues’ work could inspire a tool to compare interventions that may influence the makeup of a child’s gut microbiome.

The team is now studying the microbiota of children in several countries, including South Africa, Brazil, and Peru. The researchers hope the results bolster their initial findings from Bangladesh and Malawi in the coming months. These studies are part of a larger effort to develop bacteria-mediated interventions that can restore gut microbiome function in malnourished children. Gordon noted that there may be windows of opportunity to rebalance the gut microbiota early on, raising the possibility of reducing some of the lingering effects of early childhood malnutrition.

S. Subramanian et al., “Persistent gut microbiota immaturity in malnourished Bangladeshi children,” Nature, doi:10.1038/nature13421, 2014.

Source: The Scientist

Pharmalot blogs back

According to The Scientist, Ed Silverman’s Pharmalot blog is back, with a new home at The Wall Street Journal. Earlier this year (January 2), the blog was shut down by its former parent company, UBM Canon, which shuttered a handful of websites including PharmaLive.com, on which Pharmalot once resided.

In a June 3 post, Silverman said he will continue to cover the pharmaceutical and biotech industries as he has in the past. “And the subject matter will continue to touch on many topical bases—successes and failures as told by executives and patients; R&D challenges; patent skirmishes; marketing wars; government oversight; the use of social media and pricing tussles with payers, to name a few,” he wrote.

Posted by Tim Sandle

New microscope in development

Scientists rely heavily on incubators and microscopes. With this in mind the Fraunhofer Institute for Biomedical Engineering IBMT has come up with a novel solution that combines the functions of both these tools in a compact and extremely small-scale system. It is ideally suited for time-lapse examination over a number of weeks and for automatic observation of cell cultures. The incubator microscope is no bigger than a soda can and costs 30 times less than buying an incubator and a microscope separately. It will be on display for the first time at MEDTEC in Stuttgart.

Cultivating human and animal cells requires parameters such as temperature and humidity to be specified with absolute precision and maintained at an even level over long periods of time. Time-lapse observation over a period of some weeks can be particularly valuable, since a lot happens in that time in terms of cell reproduction and differentiation. Until now, the usual technique to make these sorts of observations has been to use small incubators in combination with conventional microscopes. This takes up about one square meter of space, making operating several such systems alongside each other an inefficient process. There is a need for innovative solutions that will significantly reduce the space needed and the costs involved -- without compromising the quality of the cultivation and of the microscope images recorded.

The new technology includes a small-scale incubation chamber and control electronics to ensure defined cell culture parameters. Cells grow on the floor of the miniaturized incubation chamber on a thin, replaceable glass plate and are supplied with a constant stream of nutrients. The only parameters that need to be kept constant within the incubator are the temperature and the nutrient supply flow rate. All in all, the small-scale incubator microscope is extremely good value and allows for many units to be operated in parallel in a very compact space. And despite its space-saving design, the system yields images that are almost as good as those of the big microscopes.

Posted by Tim Sandle

Culturing microorganisms

For over 100 years microbiologists have known, to their great consternation, that in any given environment, at least 90% of all microbes are unculturable. In the last few decades, we have developed molecular tools to see these microbes in the environment and determine their presences and number, but we still cannot bring them into culture. There are all sorts of ideas for why this might be true. Many of these microbes may be slow growing, and the fast growing microbes easily outpace them in laboratory medium. Maybe the media we use is "too rich" for many microbes and we need to create media with more dilute nutrients to capture these shy microbes. Maybe the metabolic demands of these microbes were too difficult to replicate in the laboratory and many of them will not grow. Whatever the reason, as of right now, we are nearly blind when it come to these unculturable microbes.

A landmark paper was published a year ago in Applied and Environmental Microbiology. Buerger et. al created a simple, elegant experiment to try to capture the slow-growing bacteria. Sediment from the ocean shore of Massachusetts Bay was diluted and then dispensed into wells of a microtiter plate such that each well received only 1 microbe per well. The growth medium used was 0.1x LB medium, a dilution of a common, rich medium. The plates was carefully wrapped and placed in a humidified chamber for 18 months. Yes, that is a 1.5 year experiment! Periodically the plates were checked for growth and any well showing growth was then characterized.

The expected result was that the slow-growing microbes would arrive later and the number of novel species isolated would increase as the length of the incubation increased. This would fit the hypothesis that the slow growers were being out competed. To their surprise, this was not the case. As the experiment went on, the percentage of novel species did not increase, but stayed remarkably similar. In addition, bacteria isolated by this technique did not grown much slower than microbes that have been cultivated for many years. Buerger et al. hypothesize that cells in the environment may be in a dormant state, and only randomly emerge from this state and grow. This "Scout Hypothesis" would explain the results that they were seeing. They also did a similar experiment on a soil sample and observed similar results

The implication of this experiment is that it should be possible to isolate and characterize many more unculturable species using very simple, and inexpensive techniques. Given enough experimentation, scientists may be able to culture a much larger proportion of the species present in an environment.
Posted by Paustian

Mobile genetic elements in bacteria and archaea

Researchers uncover a group of mobile genetic elements in bacteria and archaea encoding a Cas enzyme. Transposons are stretches of DNA that can hop to different sites in the genome and are commonly found in many types of organisms. In a study published in BMC Biology, researchers described a new type of transposon-like element in bacteria and archaea that encodes a Cas enzyme—well appreciated for its role in the CRISPR/Cas adaptive immune system in prokaryotes—which it in turn requires for integrating into a new genomic home.

As an immune response, CRISPR/Cas works by targeting and chopping up foreign DNA, and labs around the globe have adapted it for genomic editing purposes using the enzyme Cas9.

Casposons are now the second family of transposons—aside from a group present in eukaryotic genomes—known to be self-synthesizing, meaning that they code for their own DNA polymerase involved in replication.

Posted by Tim Sandle

Bacillus cereus infections (update)

Publication of the main findings from the PHE and MHRA investigation into the Bacillus cereus outbreak in the U.K. (issued by Public Health England).

Public Health England (PHE) and the Medicines and Healthcare products Regulatory Agency (MHRA) are in the final stages of their investigations into the outbreak of Bacillus cereus in the implicated intravenous liquid (Total Parenteral Nutrition, TPN).

Since the last update on 12 June 2014, a further case has been identified and the total number of cases linked to this investigation is 23 (19 confirmed and 4 possible cases). This baby has sadly died and our thoughts are with the family. This is the third confirmed case to have died and all 3 cases have been reported to the coroner.

The baby most recently identified received the implicated batch of TPN from 27 May 2014 but did not immediately develop sepsis so did not fit the case definition of the outbreak at that time. However, recent microbiological tests have shown the presence of the outbreak strain.

The strain of Bacillus cereus identified in the 19 cases confirmed as infected, has also since been identified in environmental samples collected from the day of manufacture (27 May 2014), located within the particular sterile area at ITH Pharma where the specific TPN supplies were manufactured. These specific TPN supplies were recalled by the MHRA on 4 June 2014.

Bacillus cereus is a common bacteria found widely in the environment in dust, soil and vegetation. Bacillus cereus produces very hardy spores, which make it persistent in the environment. Under certain conditions, the bacteria produces a number of toxins which can cause illness.

There is sufficient scientific evidence to indicate that the contamination was introduced into these specific TPN supplies during manufacture in a particular sterile manufacturing area at ITH Pharma on 27 May 2014 and MHRA’s investigations of the production process of TPN have found no evidence to suggest that individual ingredients, components or materials used were the cause of the contamination.

The MHRA has inspected ITH Pharma’s manufacturing facility and undertaken a rigorous and thorough review of the manufacturing processes and conditions within which the specific TPN supplies were manufactured. Based on the information obtained, there is sufficient evidence to indicate an isolated incident. Appropriate immediate action has since been taken at ITH Pharma’s facility to avoid a recurrence. The MHRA continues to allow TPN, a critical product, to be manufactured at ITH Pharma and therefore be supplied to patients.

Unopened supplies of the contaminated TPN (manufactured on 27 May 2014 at ITH Pharma) were collected from a few hospitals and these have been confirmed to contain the same strain of bacteria. Other tests on unopened TPN products manufactured by ITH Pharma after 27 May 2014 have all been clear of the bacteria.

A public health investigation that compared 18 confirmed cases with a comparison group of babies who did not have the outbreak strain of Bacillus cereus demonstrated a highly significant association between receiving TPN manufactured on 27 May 2014 and being infected by the outbreak strain.
Professor Mike Catchpole, PHE Incident Director, said:

"There are still some elements of our investigation that need finalising but the main findings have all pointed towards there being a single incident that occurred on one day and was associated with the illness seen in the babies. We are reassured that this was a very rare occurrence as we have not seen this particular strain of bacteria in any product made since that day and there has been no further illness."

Gerald Heddell, the MHRA’s Director of Inspection, Enforcement and Standards, said:

"At this stage, our investigation has provided sufficient evidence to indicate that the contamination was introduced into the specific Total Parenteral Nutrition (TPN) supplies during manufacture in a particular sterile manufacturing area at ITH Pharma on the 27 May 2014.
There is no evidence to suggest that individual ingredients, components or materials used for the manufacture of TPN on 27 May 2014 were the cause of the contamination. However, what we do know from our investigation is that the strain of Bacillus cereus which infected the babies has also been identified at ITH Pharma’s manufacturing facility and within some of the unopened TPN supplies manufactured on the 27 May 2014. 

From our investigation to date, we continue to believe this was an isolated incident and that appropriate immediate action has been taken at ITH Pharma’s facility to avoid a recurrence. Therefore we are allowing this critical product to be supplied to patients while our investigation continues."

Posted by Tim Sandle