Monday, 31 October 2016

Risk Assessment and Management for Healthcare Manufacturing

Tim Sandle has published a new book titled “Risk Assessment and Management for Healthcare Manufacturing: Practical Tips and Case Studies.”

Avoidance of hazards and assessment of risk have long been part of the manufacture of pharmaceuticals and healthcare products. A high quality drug product must be free from contamination and reliably deliver the intended therapeutic dose as stated on the label and to achieve this manufactures must always be mindful of risk.

Tim Sandle's newest book incorporates regulatory perspectives, scientific methods and practical examples to describe approaches to problem solving when assessing, managing and reviewing risk. The book is divided into four sections that present a formal approach to risk. The first section provides a look at risk assessments and hazards, exploring the origins, looking at key concepts and philosophies and assessing the regulatory perspective. An overview of available tools for risk assessment and problem solving leads into specific 'soft skills' that can help to run an effective meeting, oversee a project and report root cause analysis and risk outcomes. The book concludes with an extensive set of case studies to show real-world applications of the tools and techniques presented. The wide range of topics presented throughout the four sections includes risk considerations for aging pharmaceutical facilities, application of quality risk management to cleanroom design and process incident investigation.

Further details about the book and ordering details can be found via the PDA Bookstore:

The contents of the book are:

Part A: Risk Assessment and Hazards
  • Risk Assessment and Risk Management
  • Regulatory Perspectives on Risk
  • Pharmaceutical Processing Hazards
  • Root Cause Analysis

Part B: Risk Assessment Tools and Problem Solving Approaches
  • Question Based Approaches: The "Five Whys" and "What if" Methods
  • Is/Is not Approach
  • Simple Risk Assessment Tools
  • Fishbone (Ishikawa) Diagram
  • Contradiction Matrix and Knot Charts
  • Pareto Charts and Control Charts
  • Hazard Analysis and Critical Control Points
  • Failure Modes and Effects Analysis
  • Monte Carlo Method
  • Fault Tree Analysis
  • Hazard and Operability Study
  • Six Sigma and Associated Quality Tools

Part C: Practical Tips
  • Effective Meetings and the Process of Brainstorming
  • Project Management and Research
  • Reporting Risk Outcomes

Part D: Case Studies
  • Application of Quality Risk Management to Cleanroom Design
  • Case Study: Hepa Filter Failure
  • Aseptic Transfer Risk Assessment: A Case Study
  • Importance of Risk Assessment for Aseptic Transfer in Pharmaceutical Compounding
  • Risk Assessment for Intervention Scoring in Relation to Aseptic Processing
  • General Considerations for the Risk Assessment of Isolators Used for Aseptic Processes
  • Risk Considerations for the Use of Unidirectional Airflow Devices
  • Risk Consideration for Aging Pharmaceutical Facilities
  • Process Incident Investigation
  • Addressing Manufacturing Constraints by Increasing Production Throughput
  • Risk Assessment of Production Formulation Stages
  • Risk Based Approach to Internal Quality Auditing
  • Risk Assessment for Data Integrity
  • Assessment of Raw Material Handling and Expiration
  • Risk Management and the Supply Chain
  • Risks Associated with Clinical Trials
  • Application of Risk Assessment to Develop an Environmental Monitoring Program
  • Detection and Risk: Environmental Monitoring Data Deviations
  • Application of Risk Assessment for Personnel Safety
  • Risk Considerations for the Installation of a New Pharmaceutical Facility Autoclave
  • Safety Risk Assessment for the Ozonation of a Purified Water System
  • Error Risk Reduction: Concept and Case Study

The reference is:

Sandle, T. (2016) Risk Assessment and Management for Healthcare Manufacturing: Practical Tips and Case Studies, PDA / DHI, Bethesda, MD, USA.

Posted by Dr. Tim Sandle

Sunday, 30 October 2016

Shingles And Asthma Linked Together

A new study has connected shingles to increased rates of acute cardiovascular events such as ischemic stroke. The same research, from the Mayo Clinic, has drawn a connection between developing shingles and asthma.

Shingles (caused by the virus herpes zoster) is a disease characterized by a painful skin rash with blisters. Symptoms include a burning rash, together with headache, fever, and malaise.

Moreover, research indicates that childhood asthma to be linked to higher risk of developing shingles as an adult. This was derived at after a review of medical records from adults aged 50 and over from Olmsted County, Minnesota. These data were cross-referenced with the frequency of asthma in people diagnosed with shingles.

It was found that the mean (average) age of the patients with shingles was 67 years. Using logistic regression, the researchers calculated that adults who had asthma had a 70% higher risk of developing shingles as compared with those without asthma.

The inference from this study is that older adults with asthma should consider being immunized against shingles by vaccination.

Speaking with Medline, Dr. Young Juhn, a general academic pediatrician and asthma epidemiologist at the Mayo Clinic Children's Research Center, noted: “As asthma is an unrecognized risk factor for zoster [shingles] in adults, consideration should be given to immunizing adults aged 50 years and older with asthma or atopic dermatitis as a target group for zoster [shingles] vaccination.”

Research detailing the connection has been published in the Journal of Allergy and Clinical Immunology. The research is titled “Asthma as a risk factor for zoster in adults: A population-based case-control study.”

Posted by Dr. Tim Sandle

Saturday, 29 October 2016

Decline In UK Animal Experiments

Fewer animals were used in experiments in the U.K. during 2014 compared with 2013 (these are the latest statistics, released in January 2016 by the Home Office). The decline is 6 percent, with some 3.8 million procedures undertaken in 2014.

The primary users of animals for research is the university sector, with fewer animals used by pharmaceutical companies (many tests traditionally involving animals have been replaced by cell-based assays).

With the university sector, the main use of animals is with cancer research. In the past, it was common for animals to be used for toxicological purposes, but this type of poison screening has declined.

There remains a need to test new and experimental drugs on animals before going to human clinical trial. This does not always work out, as the recent events in France showed, when an experimental drug was tested on 90 people. Here one person died and four are in a serious condition (as reported by The Latest News.)

Animal testing in the U.K. is controlled and to practice requires the issuing of a Home Office licence, as per The Animals (Scientific Procedures) Act 1986. This applies to any procedure likely to cause that animal pain, suffering, distress or lasting harm.

Posted by Dr. Tim Sandle

Friday, 28 October 2016

Tracking the evolution of antibiotic resistance

Researchers have developed a large culturing device to track the evolution of bacteria as they mutate in the presence of antibiotics, revealing that, surprisingly, the fittest mutants were not those most likely to infiltrate higher antibiotic concentrations. Instead, bacteria "behind" the very fittest on the growth plate became capable of surviving at highest antibiotic concentrations.

The results provide important insights into the evolutionary patterns and mechanisms that drive bacteria's success in overcoming antibiotics, a phenomenon that threatens human health worldwide. To better understand the emergence of antibiotic resistance in space and time, Michael Baym and colleagues developed a device called the microbial evolution growth arena plate, or MEGA plate -- a large, rectangular petri dish across which different concentrations of antibiotics can be applied; here, the researchers used trimethoprim and ciprofloxacin.

Bacteria were cultured at one location on the plate; as competition for resources increased, they spread to other regions. Applying varying levels of antibiotics, the authors were able to map out mutations that allowed increasingly resistant mutant bacteria to spread. Bacteria were unable to adapt directly from zero antibiotic to the highest concentrations, for both drugs tested, revealing that exposure to intermediate concentrations of antibiotics is essential for the bacteria to evolve resistance.

Mutations that increased resistance often came at the cost of reduced growth, which was subsequently restored by additional compensatory mutations, the authors found. Intriguingly, the spatial location of bacterial species played a role in their success in developing resistance.

For example, when the researchers moved the trapped mutants (those behind their "fit" parents) to the "frontlines" of the culture, they were able to grow into new regions where the frontline bacteria could not. In light of this finding, the authors suggest that the fitness of bacterial populations is not driven by the fittest mutants, but rather by those that are both sufficiently fit and arise sufficiently close to the advancing front.

As Luke McNally and Sam Brown explain in a related Perspective, the MEGA plate device developed here, which provided "an unprecedented visualization of [bacterial] evolution through time and space," could be used to explore additional aspects of drug resistance evolution.

For further details see:

M. Baym, T. D. Lieberman, E. D. Kelsic, R. Chait, R. Gross, I. Yelin, R. Kishony. Spatiotemporal microbial evolution on antibiotic landscapes. Science, 2016; 353 (6304): 1147 DOI: 10.1126/science.aag0822

Posted by Dr. Tim Sandle

Thursday, 27 October 2016

The microbiome and evolution

Biotechniques have an interesting article about the gut microbiome, the Human Microbiome Project and the role that the microbiome plays in human evolution.

Here is an extract:

“Scientists have unearthed the fact that drastic differences in microbiomes can be inherited and that they can irreversibly meddle with metabolic processes. The high-fat, high-salt diet that characterizes the economic West and the overuse of antibiotics around the world have reshaped our microbiota.

If this recent divergence in our microbiomes has significantly contributed to the alarming increase in incidence of chronic diseases such as Crohn’s disease and type 2 diabetes, Justin Sonnenburg, Associate Professor of Microbiology and Immunology at Stanford predicts that it will inevitably affect our evolution. “If you were to go thousands of years into the future, I would guess that you would see that there will be a [genetic] bottleneck, and you’ll lose some of the pro-inflammatory alleles just because kids that are getting childhood Crohn’s disease for instance are going to be less reproductively fit.”

Here are some related academic papers of interest:
Round JL, Mazmanian SK. The gut microbiome shapes intestinal immune responses during health and disease. 2009. Nat Rev Immunol. 9(5): 313– 323.
Lim ES, Wang D, Holtz LR. The Bacterial Microbiome and Virome Milestones of Infant Development. The Bacterial Microbiome and Virome Milestones of Infant Development. 2016. Trends Microbiol. pii: S0966-842X(16)30064-6
Sonnenburg JL, Bäckhed F. Diet–microbiota interactions as moderators of human metabolism. 2016. Nature. 535(7610):56-64.
Diaz Heijtz R et al. Normal gut microbiota modulates brain development and behavior. 2011. Proc Natl Acad Sci U S A. 108(7):3047-52.
Moeller AH et al. Cospeciation of gut microbiota with hominids. 2016. Science. 353(6297): 380-2.
De Filippo C et al. Impact of diet in shaping gut microbiota revealed by a comparative study in children from Europe and rural Africa. 2010. Proc Natl Acad Sci U S A. 107(33):14691-6

Posted by Dr. Tim Sandle

Wednesday, 26 October 2016

EMA paper on production of water for injections (WFI) by non-distillation methods

The European Medicines Agency has published a question and answer paper on the production of water for injections (WFI) by non-distillation methods.

Water for injections in bulk is obtained from water that complies with the regulations on water intended for human consumption laid down by the competent authority or from purified water. It is produced either:

·         By distillation in an apparatus of which the parts in contact with the water are of neutral glass, quartz or a suitable metal and which is fitted with an effective device to prevent the entrainment of droplets; or
·         By a purification process that is equivalent to distillation. Reverse osmosis, which may be single-pass or double-pass, coupled with other appropriate techniques such as electro-deionisation, ultrafiltration or nanofiltration, is suitable. Notice is given to the supervisory authority of the manufacturer before implementation.

EMA/INS/GMP/489331/2016: Questions and answers on production of water for injections by non-distillation methods – reverse osmosis and biofilms and control strategies

Posted by Dr. Tim Sandle

Tuesday, 25 October 2016

UN to tackle the 'fundamental threat' of antibiotic-resistant superbugs

All 193 UN member states have agreed to combat the proliferation of drug-resistant infections, estimated to kill more than 700,000 people each year, according to The Guardian.

The UN secretary general, Ban Ki-moon, said antimicrobial resistance is a “fundamental threat” to global health and safety at the first general assembly meeting on drug-resistant bacteria.

It is only the fourth time the general assembly has held a high-level meeting for a health issue.

“If we fail to address this problem quickly and comprehensively, antimicrobial resistance will make providing high-quality universal healthcare coverage more difficult if not impossible,” said Ban. “It will undermine sustainable food production. And it will put the sustainable development goals in jeopardy.”

For more on this news item, see The Guardian.

Posted by Dr. Tim Sandle

Monday, 24 October 2016

Too much cleanliness is affecting our microbiome for the worse

Increasing concerns about personal cleanliness, especially with children, could be linked to a reduced the diversity of our microbiomes and increased the prevalence of inflammatory and stress-related diseases.

New research gives new weight to the so-called hygiene hypothesis, arguing that children, in the early years, need to be exposed to dirt (and by implication a diversity of bacteria) in order suggests to strengthen their immune system, and that such exposure increases the richness of the human microbiome (the collection of microbes that reside within the human body.)

The hygiene hypothesis explains that the marked increase in autoimmune and inflammatory diseases since the 1950s is the direct result of changes in our exposure to microbes in childhood, which runs in parallel with a reduced exposure to the less than sanitary conditions. The concept also relies on decreasing family sizes, such as having fewer siblings, which results in a reduced chance of exposure to pathogens. This remains theoretical, although the ideas are backed by a large number of scientists.

Some related research, within the broad hygiene field, has been undertaken at University of Colorado Boulder. Microbiologists and medics have been studying whether the reduced exposure to infectious agents is coincidental with an increase in inflammatory-related diseases. The effects of inflammation can lead to a higher risk of developing stress-related pathologies, like such as post-traumatic stress disorder (PTSD) and depression.

This has led to a consideration of whether stress-related disorders can be decreased (in terms of incidences or severity) by increasing a person’s exposure to environmental bacteria.

With this, lead researcher Dr. Christopher Lowry has told Bioscience Techniques: “Our approach wasn’t so much to modify the gut microbiome, but to protect the host from stress-induced microbiome changes.”

The work has involved looking at a soil bacterium called Mycobacterium vaccae. This bacterium has been linked to improved moods and lower levels of pain. To see if the bacteria can reduce stress, the research group vaccinated mice with a heat-killed preparation prior to exposing them to chronic social stress. It was observed that the bacterium did promote long-lasting and proactive coping behavior. In neurological terms, the organism could be exerting an effect on the serotonergic and microglia systems. This is, therefore, an area worthy of further exploration.

The research has been published in Proceedings of the National Academy of Sciences. The research paper is titled “Immunization with a heat-killed preparation of the environmental bacterium Mycobacterium vaccae promotes stress resilience in mice.”

Posted by Dr. Tim Sandle

Sunday, 23 October 2016

Will Big Data Influence Pharmaceuticals for the Better?

Today, it feels like everything is connected. You can access your files from a computer, a smart phone, a tablet or any other interconnected device — and that only accounts for your own personal files and devices.

Guest post by Megan Ray Nichols

Cloud storage and other big data creations have changed the way we look at and store information. What impact will these changes have on the pharmaceutical industry? Will these changes be able to alter the industry for the better, or could they possibly present new problems?

Waiting for Answers

One of the biggest problems researchers face in the pharmaceutical industry is the fact that information, in general, is treated as a proprietary and closely guarded secret. Individual researchers and companies spend a lot of time keeping their data protected from outside influence. They spend so much time protecting their information that when it comes time to share with the public, the investors, or other pharmaceutical companies, it becomes difficult or nearly impossible to disseminate the information.

Many companies have started to share their raw clinical trial information with the industry, but it’s a slow process. In the meantime, the data that might lead to the next wonder drug or medical breakthrough is sitting in limbo, gathering virtual dust because it can be so difficult to access.

Genomics and Data

One of the biggest uses for big data in the pharmaceutical industry is in the field of genomics. You need a lot of space and quite a bit of computing power to sequence a human genome — when you’re dealing with 25,000 genes and three billion base pairs of DNA, you’re looking at about 1.5 gigabytes of storage per genome sequenced. To put it in perspective, that’s about the size of a 1080p movie file.

If you’re sequencing the genomes of a couple hundred test subjects, you may find yourself carting around dozens of heavy hard drives in order to carry all of that information. Alternatively, though, you could look into cloud data storage.

The ability to share genomic data via cloud technology has two main benefits. First, it cuts down on the amount of physical storage space you need. All that’s required is a computer with Internet access to connect to all of your data.

Second, it makes it easier and faster to share raw research data with the rest of the pharmaceutical community. If a researcher in Tokyo makes a discovery that could shake the entire industry to its core, they don’t have to sit through the peer review process, waiting weeks or months to publish a paper that could change the world. All they have to do is upload their research to the cloud. It’s as simple as that.

Now, most researchers aren’t uploading their publishable discoveries, preferring instead to share their raw research data, but the platform is still there to provide a stepping stone for genomic data discoveries.

Quantifying Data

While cloud storage is a great platform for sharing research data, that’s not the only thing it’s good for. It can also be used to help researchers quantify the raw data that has been placed in the cloud.

Having sequenced genome information stored for a variety of different subjects is great, but it can be a bit daunting to sift through if you’re specifically looking for subjects of a specific race, gender or age.

Cloud storage, when paired with a little bit of simple software, allows researchers to search through the stored data to find specific traits without having to pick through each individual genome to find what they’re looking for. Cambridge Semantic’s program Semantic Web is just one of the tools researchers can use to sift through the raw data to find the traits they’re looking for.

Crowdsourcing Our Genetics
Crowdsourcing has become a great tool for people who need to raise money, gather information, or in many cases, even make dramatic scientific discoveries. Stanford’s Folding@Home Project, for example, has been using personal computers around the globe for 16 years to find the answers to puzzles that have otherwise eluded scientists.

FoldIt, on the other hand, is a more interactive game that allows users to actively work toward the solution rather than watching the proteins passively fold. In 2011, users found the answer to a problem that had eluded scientists for 15 years. The amazing part is that collectively, FoldIt players were able to find the answer in three weeks.

If big data can do that for the pharmaceutical industry while just using random Internet visitors, imagine what they could do with a crowd of industry professionals around the globe?

Risks vs. Rewards
Bringing big data into the pharmaceutical industry has the potential for great rewards. Unfortunately, whenever you bring the Internet into the data equation, there’s always some risk as well.

The first risk you take is that the data you’re going to find is just random junk with no real use or application. Even if you severely limit the number of people who can access your data cloud, there’s still a chance that someone will upload some useless data that could potentially skew any and all results.

The second, and arguably the most dangerous risk, is data privacy. All it takes is one person with nefarious intentions gaining access to your data cloud, and all of your patient’s information could be at risk. Hackers are targeting medical information now more than ever because it’s more valuable than credit card information and not checked nearly as often.

It is possible to reduce this risk by removing personal information from the data, beyond the bits of information needed to classify the raw information. Removing names, insurance information and other personal identifiers can help to protect your subjects while still allowing you to take advantage of the raw study data.

What It Means for Big Data and Pharmaceuticals

Overall, the use of Big Data in the pharmaceutical industry is going be a force for great good and the launching point for many ingenious advances in the industry. There’s no telling what amazing things will fall from that cloud next!

The Latest Xarelto Lawsuit Update

In 2011, the Food and Drug Administration (FDA) approved a blood thinner called Xarelto for use in various medical situations. Since Xarelto was approved, manufacturer Janssen Pharmaceuticals has filled over three million orders for the medication. In August 2013, the FDA started issuing warnings about the use of Xarelto after it had received over 2,100 adverse event complaints about the medication. Furthermore, states that by May 2015, 400 lawsuits were transferred to the MDL in Louisiana and nearly 100 lawsuits were filed in Philadelphia.

What Is A Blood Thinner?

A blood thinner prevents the blood from clotting both internally and in open wounds. Xarelto blocks the thrombin in the blood that causes clotting, and that is designed to help patients who are at risk of getting blood clots. Blood thinners are designed to prevent dangerous leg and lung blood clots, and they also help to prevent strokes.

What Went Wrong With Xarelto?

Xarelto has been tagged as the primary cause of serious internal bleeding cases around the country with some of the cases leading to the death of the patient. When the blood cannot clot internally, it collects throughout the body and creates a variety of serious medical issues. While all blood thinners come with inherent risks, it became obvious that Xarelto created more of a risk than the majority of blood thinners on the market.

Has The FDA Done A Recall On Xarelto?

Once the FDA has officially approved a drug for resale, it is very hesitant to recall the drug without proof of significant harm to the public. In the case of Xarelto, the FDA has not yet issued any type of recall as of October 2016. The FDA has issued:
  • Two black box warnings (large black labels put on the product packaging as a warning) in August 2013 and December 2014 
  • A January 2014 warning against the use of Xarelto in certain medical situations and a statement that there is no antidote for Xarelto once it is in the patient's system 
  • A March 2014 warning recommending that patients on Xarelto wait until the drug is out of their system before having any spinal procedures done 
What Are The Latest Developments In The Xarelto Situation?

On January 15, 2016, it was reported that there are 2,826 lawsuits pending in regards to internal bleeding issues caused by Xarelto. When the FDA will not recall a drug, the only solution for victims is to file a lawsuit. When an excessive amount of lawsuits are filed, legal authorities will usually try to either create a class action suit or allow certain cases to go forward that are indicative of the majority of the lawsuits filed, also referred to as bellwether trials.

In August 2016, the FDA rejected an application from Portola Pharmaceuticals to move forward with an antidote for Xarelto. To this point, no application by any company to develop an antidote has been accepted.

The first bellwether trials were scheduled to take place in the fall of 2016 in New Orleans. But on September 21, 2016, those trials were officially delayed because the NBA All-Star game was to be played in New Orleans around the time of the trials and officials felt that having those two events taking place at the same time would be a logistical nightmare.

On October 3, 2016, the Journal of the American Medical Association published a side-by-side comparison between Xarelto and the blood thinner Pradaxa. Their conclusion was that serious bleeding events were much more common with Xarelto than with Pradaxa.

It was revealed that 80 bellwether cases are going to be scheduled to be heard in New Orleans at some point in early 2017. At the same time, it is estimated that another 800 lawsuits could start against Janssen Pharmaceuticals in the Philadelphia Complex Litigation Center. Janssen is already involved in several other cases regarding some of its other medications in the Philadelphia Complex Litigation Center.

When the FDA will not ban or recall a drug, victims feel it necessary to file lawsuits to get justice. Starting in early 2017, we will be able to see whether or not victims of Xarelto will get the justice they feel they deserve.

About Michael Monheit, Esq.

Michael Monheit, the managing attorney at Monheit Law, has been working to assist individuals and families who have been harmed by defective drugs and products. In fact, Mr. Monheit served on the Plaintiff’s Steering and Executive Committee for MDL 1148. He understands how stressful it can be to stand up to a major corporation and is committed to making sure that plaintiffs know they have someone on their side.

Rapid method for detecting foodborne pathogens

Researchers have developed a hybrid nanosensor incorporating magnetic resonance and fluorescence. Lab testing of milk showed the detector could sense varying concentrations of a pathogenic strain of E. coli known as O157:H7 in less than an hour. They also used their sensor to analyze E. coli levels in untreated lake water, which serves as a source of household water in some developing areas. Additionally, the device could be customized to detect a wide range of pathogens beyond E. coli.

For further details see:

Tuhina Banerjee, Shoukath Sulthana, Tyler Shelby, Blaze Heckert, Jessica Jewell, Kalee Woody, Vida Karimnia, James McAfee, Santimukul Santra. Multiparametric Magneto-fluorescent Nanosensors for the Ultrasensitive Detection ofEscherichia coliO157:H7. ACS Infectious Diseases, 2016; DOI: 10.1021/acsinfecdis.6b00108

Posted by Dr. Tim Sandle

Saturday, 22 October 2016

Moist-heat sterilization of blood bags

Vittorio Mascherpa has written an interesting article on the sterilization of blood collection bags. The abstract reads:

“This article provides basic information on the sterilization of blood bags systems by moist-heat. Problems of pressure compensation and steam penetration into the system parts without water inside, and the process choice between single and double autoclaving are discussed.”

The article can be accessed here.

Posted by Dr. Tim Sandle

Friday, 21 October 2016

EMA Determines Certain Drugs Safe from Zika Contamination

On Sept. 21, 2016, the European Medicines Agency (EMA) announced there is no increased risk of Zika contamination for patients who take plasma- or urine-derived drugs. The conclusion was made after an assessment was carried out by EMA and authorities in EU Member States to determine if drugs produced from body fluids, which might be sourced from parts of the world where Zika is prevalent, could contaminate the final product with the virus.

EMA’s Committee for Medicinal Products for Human Use (CHMP) concluded that manufacturing processes such as solvent/detergent methods, pasteurization, and virus filtration inactivate or remove the Zika virus from the finished product. Steps for the inactivation/removal capacity for enveloped viruses are included in the manufacturing processes for urine-derived products. CHMP considers these steps sufficient to keep patients safe from Zika contamination.

According to EMA, plasma-derived drugs, which are manufactured from human blood, include coagulation factors and immunoglobulins. Urine-derived products, which are manufactured from pooled human urine, include hormone-based treatments and urokinase products.

Posted by Dr. Tim Sandle

Thursday, 20 October 2016

WHO guidance on variations to multisource pharmaceutical products

The World Health Organization has updated Annex 10 of its GMPs “WHO general guidance on variations to multisource pharmaceutical products.”

According to the document:

“A marketing authorization (MA) holder or applicant is responsible for the quality, safety and efficacy (QSE) of a finished pharmaceutical product (FPP) that is placed on the market, throughout its life cycle. After the FPP has been authorized for marketing, the manufacturer will often wish to make changes (variations) for a number of reasons, for example, to respond to technical and scientific progress, to improve the quality of the FPP, to apply updates to the retest period for the active pharmaceutical ingredient (API) or shelf life of the FPP, to meet market requirements such as for scale-up or additional manufacturing sites, or to update product information (e.g. the information on adverse reactions). Such changes, regardless of their nature, are referred to as variations and may require the approval of the national medicines regulatory authority (NMRA) prior to implementation.”

The document can be accessed here.

Posted by Dr. Tim Sandle

Wednesday, 19 October 2016

History of Pharmig

The history of the Pharmaceutical Microbiology Interest Group (Pharmig)

Posted by Dr. Tim Sandle

Tuesday, 18 October 2016

A new, epidemic strain of C. difficile is proving deadly

A new, epidemic strain of C. difficile is proving deadly, and new research from the University of Virginia School of Medicine not only explains why but also suggests a way to stop it.

Until now, scientists have not understood what made this strain worse than other strains of the bacteria, the most common cause of hospital-acquired infections. The new strain kills up to 15 percent of infected patients, including those who receive antibiotics, and has become increasingly common over the last 15 years. This has prompted the federal Centers for Disease Control and Prevention to label it an "urgent threat."

The finding comes from the lab of Bill Petri, MD, PhD, chief of UVA's Division of Infectious Diseases and International Health, and a team of international collaborators. PhD student Carrie A. Cowardin was working in Petri's lab when she discovered the diabolical mechanisms this strain of C. diff uses to overcome the body's natural defenses.

The strain is so deadly because it produces a toxin that kills protective cells, called eosinophils, found in the gut, Cowardin found. By destroying the gut's natural barrier, the bacteria can spread inflammation throughout the body. "We think that this toxin makes disease more severe by killing beneficial eosinophils, which seem to play an important role in promoting a healthy immune response during C. difficile infection. When the eosinophils were depleted with an antibody or by the toxin, we saw dramatically increased inflammation. Restoring eosinophils by transferring them from a mouse that cannot recognize the toxin prevented the damage inflicted by the epidemic strain," said Cowardin, now a postdoctoral fellow at Washington University in St. Louis. "This builds on previous work in our lab showing that eosinophils are beneficial and suggests that one reason this strain causes such severe disease is due to its ability to kill these cells."

Further, Cowardin discovered exactly how the toxin works, and how well it functions in this role. The toxin, she determined, requires a particular human protein that recognizes bacteria, a protein that plays a key role in the immune response. In short, C. diff is subverting the body's natural defenses to overcome those defenses.

This understanding of the toxin's action could be of great importance, as blocking it can rescue the protective cells in the gut. And that approach could lead to a new treatment to stop this deadly strain of C. diff in its tracks.

"Nearly every day that I care for patients I am faced with this potentially deadly infection," Petri said. "Carrie Cowardin's discovery of why this strain of C. diff is so dangerous, and most importantly how to combat it, is a huge and most needed advance."


Carrie A. Cowardin, Erica L. Buonomo, Mahmoud M. Saleh, Madeline G. Wilson, Stacey L. Burgess, Sarah A. Kuehne, Carsten Schwan, Anna M. Eichhoff, Friedrich Koch-Nolte, Dena Lyras, Klaus Aktories, Nigel P. Minton, William A. Petri. The binary toxin CDT enhances Clostridium difficile virulence by suppressing protective colonic eosinophilia.Nature Microbiology, 2016; 1 (8): 16108 DOI:10.1038/nmicrobiol.2016.108

Posted by Dr. Tim Sandle

More flexibility for authorisation of biocidal products

News on the regulation of biocides in Europe:


The regulation on the authorisation of same biocidal products has been updated to add new possibilities requested by industry. Companies are now able to get a national authorisation when a Union authorisation application exists for an identical product. The regulation will enter into force on 1 November.

Helsinki, 12 October 2016 – The Same Biocidal Products Regulation lays down a procedure for companies to get a secondary authorisation for a product based on either an existing authorisation or an on-going authorisation application for an identical product.
  • Following the update of the regulation, companies can now also use this authorisation procedure for:
  • a product when it is part of a product family for which an authorisation (or authorisation application) exists;
  • a product family when it is part of a larger product family for which an authorisation (or authorisation application) exists;
  • national authorisation when a corresponding Union authorisation (or authorisation application) exists.
The regulation was updated by the European Commission after a request from industry stating that the changes would help reduce the costs and administrative burden for companies.

The regulation was published in the Official Journal of the European Union on 12 October and will enter into force on 1 November 2016.

To allow for the new possibilities, ECHA will launch updated versions of the biocides IT tools – R4BP 3 and the SPC Editor – when the regulation enters into force.

Support will be available: a new web page, a practical guide and updated submission manuals will be published and a webinar on this topic will take place on 9 November 2016.

Source: ECHA

Posted by Dr. Tim Sandle

Monday, 17 October 2016

Control of WFI and Clean Steam Systems for Bacterial Endotoxins

Bacterial endotoxin presents a risk to several classes of pharmaceutical product, with parenteral products at the greatest risk. Bacterial endotoxin is the lipopolysaccharide (LPS) component of the cell wall of Gram-negative bacteria. It is pyrogenic and it is a risk to patients who are administered intravenous and intramuscular preparations. The pathological effects of endotoxin, when injected, are a rapid increase in core body temperature followed by extremely rapid and severe shock. In some cases, death can occur.

This is the topic of a new paper by Tim Sandle.

The reference is:

Sandle, T. (2016) Control of WFI and Clean Steam Systems for Bacterial Endotoxins, Journal of GxP Compliance,  20 (4): 1-15

For further details, contact Tim Sandle

Posted by Dr. Tim Sandle

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