Monday 30 September 2013

Pharmacopeial Forum new editions

Two new editions of the Pharmacpeial Forum has recently been issued (Vol. 39, No.4 and Vol. 39 No.5). Amongst the items of interest are:

Chapter111     Design and Analysis of Biological Assays (Revision proposal target, USP37-NF32 2S)

USP has developed four general information chapters pertinent to bioassays:  1030, 1032, 1033, and 1034. The latter three became official August 1, 2012, and 1030 will become official December 1, 2013. These new chapters largely replace the current general chapter 111. It is now proposed to replace the current 111 with a completely revised 111 that covers a much reduced set of topics appropriate for a chapter numbered below 1000.

Chapter 1240  Virus Testing of Human Plasma for Further Manufacture
(Revision proposal target, USP37-NF32 2S)

Human-plasma-derived products are manufactured from donated human plasma and include many therapeutically important medicines. The scope of this new general information chapter is virus testing performed on human plasma for further manufacture of pharmaceuticals. The chapter also contains an Appendix with regulatory guidances and references that support the recommendations.

Chapter 791    pH (Revision proposal target, USP37-NF32 2S)

This chapter is being updated to include contemporary terminology and modern operating procedure of pH sensors and measuring systems, to increase flexibility in the selection of pH buffers used for calibration, and to harmonize the calibration requirements with European Pharmacopoeia. There is a change in the calibration procedure and performance requirement to support a harmonized method and accuracy.

Posted by Tim Sandle

Sunday 29 September 2013

Microbiology in the News

Some useful resources.

American Society for Microbiology News Room
The latest research from ASM journals, microbiology news and government reports.
Centers for Disease Control and Prevention Home Page
Center for Disease Control: Division of Media Relations Home Page Current news events and topics in medical microbiology from the U.S. Center for Disease Control and Prevention.
Center for Disease Control: Scientific Data, Surveillance, Health Statistics, and Laboratory Information
Watching Science. Monthly listings of science news sources available on the Web, on television and on the radio.
EurekAlert A comprehensive news server for up-to-date research in science, medicine, and technology. Updated daily.
The Science Updates Archive - from Access Excellence
Science Update. Weekly updates from laboratories around the world.
The WHY Files: The Science Behind the News is an electronic exploration of the science behind the news. Twice a month, a new feature on the science of everyday life is added. (A project from the National Institute for Science Education and the University of Wisconsin-Madison).
Bugs in the News!
Online Publications
Scientific American
Nature Magazine's Science Update. News and features on the latest developments in scientific research tailored to the general reader. Articles are updated weekly.
Science Magazine. The full text and graphics of Science magazine is now online. Published by the American Association for the Advancement of Science.
Welcome to THE SCIENTIST The News Journal for the Life Scientist.

Posted by Tim Sandle

Saturday 28 September 2013

Microorganisms in the 'dark ocean'

Microorganisms that live in the so-called "dark ocean", below a depth of some 600 feet where light does not penetrate, acquire their energy from carbon fixation. That is one of the findings of a paper published in the International Society of Microbial Ecology (ISME) Journal.

In the dark ocean, carbon fixation can occur with reduced chemical energy sources such as sulfur, methane, and ferrous iron. Indeed sulfur-oxidizing microorganisms are often dominant in hydrothermal vent plumes, where they convert carbon dioxide to biomass.

For further details, refer to the following paper:

Timothy E Mattes, Brook L Nunn, Katharine T Marshall, Giora Proskurowski, Deborah S Kelley, Orest E Kawka, David R Goodlett, Dennis A Hansell, Robert M Morris. Sulfur oxidizers dominate carbon fixation at a biogeochemical hot spot in the dark ocean. The ISME Journal, 2013; DOI: 10.1038/ismej.2013.113

Posted by Tim Sandle

Friday 27 September 2013

Cryptococcus gattii and the spread of infection

Cryptococcus gattii is a type of fungus that was previously only found in warmer climates throughout the tropics. However, since 1999 outbreaks of highly virulent strains of the fungus have been reported in the cooler climes of Canada and Northwestern USA, causing serious illness in otherwise healthy people and domestic and wild animals and proving fatal in some cases.

C. gattii is found in the soil and in association with certain trees such as eucalyptus, pine or fir trees. It is transmitted to humans and other animals by inhaling spores of the fungus that are carried in the air. After infecting the lungs, cells of the fungus can travel through the bloodstream to infect other areas of the body, including the brain. The most common symptoms are shortness of breath, coughing, fatigue, fever, and headache.

To try to understand how likely it is that the disease will spread further, a team of researchers in the US and UK interbred different strains of the fungus to test how easily the characteristics of these more dangerous strains can be transferred to other less harmful strains.

The results show that genes conferring traits that make the fungus more dangerous are easily passed to the offspring when the two parent strains are closely related. When the strains are distantly related to each other, the genes are much less likely to spread.

To read more about this research, see the following paper:

Kerstin Voelz, Hansong Ma, Sujal Phadke, Edmond J. Byrnes, Pinkuan Zhu, Olaf Mueller, Rhys A. Farrer, Daniel A. Henk, Yonathan Lewit, Yen-Ping Hsueh, Matthew C. Fisher, Alexander Idnurm, Joseph Heitman, Robin C. May. Transmission of Hypervirulence Traits via Sexual Reproduction within and between Lineages of the Human Fungal Pathogen Cryptococcus gattii. PLoS Genetics, 2013; 9 (9): e1003771 DOI: 10.1371/journal.pgen.1003771

Posted by Tim Sandle

Thursday 26 September 2013

Ozone Sanitized Pharmaceutical Water Systems

The IPSE have a new guide out for the ozonation of pharmaceutical water systems. The brief for the guide runs:

“Over the past three decades, for the most part, the system designs and equipment involved in ozone sanitization have been refined and improved significantly so that current installations are both effective and reliable. Yet one specific area, ozone gas venting, has remained primarily unchanged and can still be somewhat problematic. This Knowledge Brief provides an overview of tank venting concerns and discusses design considerations addressing these concerns.”

For further details see: IPSE

Posted by Tim Sandle

Wednesday 25 September 2013

Understanding sterile filtration

An article on filtration of interest, understanding sterile filtration.

The removal of microorganisms from fluids by passage through filters is a complex process, and careful attention must be paid to the selection and validation of the filters, according to Dr Tim Sandle:

"The removal of microorganisms from fluids by passage through filters is a very complex process and is dependent on interactions relating to the chemistry and surface characteristics of the membrane, the micro-organisms, and the suspending fluid. The selection of a membrane filter for a particular product or process is an important choice and one that requires an assessment of the filter, the chemical nature of the product and the physical demands that will be placed on the filter."

Read more at: Cleanroom Technology

The reference is:

Sandle, T. (2012). Making the grade in filters, Cleanroom Technology, December 2012, pp19-20

For more details, see Cleanroom Technology or contact Tim Sandle for a copy

Posted by Tim Sandle

Tuesday 24 September 2013

Copper prevents growth of bacteria in HVAC systems

Dr Michael Schmidt, professor and vice chairman of microbiology and immunology at the Medical University of South Carolina, and his team have published a new study evaluating the efficacy of copper in reducing contamination in Heating Ventilation and Air Conditioning (HVAC) systems.

In relation to this, Cleanroom Technology has an interesting feature about the use of copper in HVAC systems as a microbial reduction measure. The conditions in many HVAC systems would appear to be ideal environments for the growth and propagation of microorganisms.

The researchers conducted a comparative study where heat exchangers fabricated from either antimicrobial copper or aluminium were evaluated for their ability to limit microbial growth, using a full-scale HVAC system under conditions of normal flow rates using single-pass outside air.

It was found that commonly-used aluminium components developed stable biofilms of bacteria and fungi within four weeks of operation, whereas the antimicrobial properties of metallic copper were able to limit the bacterial load associated with the copper heat exchanger fins by 99.99% and the fungal load by 99.74% during the same time period. Contaminants accumulate on heat exchanger coils and fins, in condensate drain pans, on air filters, and in air ducts. Indoor surfaces and building occupants can then be exposed to bio-aerosols from these sites.

To test the impact of copper surfaces, chilled water was circulated through the experimental heat exchangers. After a week the system was temporarily stopped and 99 coupons of either copper or aluminium were installed into four equivalent copper and aluminium heat exchangers. Triplicate sets of coupons were then removed from each exchanger four weeks after their installation.

The data supports the view that, when copper is substituted for aluminium in the construction of the heat exchangers, a substantial and significant reduction in the biofilm associated with the heat transfer device found in HVAC systems can be achieved.
Posted by Tim Sandle

Monday 23 September 2013

Bacteriotherapy to combat chronic C. difficile infection

A technique that restored the normal intestinal microflora in a mouse model of Clostridium difficile infection may lead to the design of an effective therapy for this highly contagious and tenacious infection in humans, according to researchers in London. They identified bacteria in the intestines of healthy mice that helped to re-establish the proper balance of microflora when given to infected mice. 

"This approach is completely novel in that we can restore the microflora and in that way develop a more rational approach to treatment," said Brendan W. Wren, FRCPath, a professor of microbial pathogenesis at the London School of Hygiene and Tropical Medicine, at a press briefing about the research. 

Although Dr. Wren was not an author of the paper describing this mouse study (Lawley TD, Clare S, Walker AW, et al. Targeted restoration of the intestinal microbiota with a simple, defined bacteriotherapy resolves relapsing Clostridium difficile disease in mice. PLoSPathog. 2012;8(10):e1002995), he has been a collaborator with the authors on previous studies investigating C. difficile 

Chronic, relapsing C. difficile can be a stubborn infection, resistant to treatment with vancomycin. Treatment of infected mice with feces from healthy mice restores healthy microbiota and resolves the disease. The researchers identified a mixture of six intestinal bacteria from healthy mice that helped to re-establish healthy microbiota in infected animals. They sequenced the genomes of these health-inducing bacteria to identify them precisely. 

"We're in a new era for the treatment of C. difficile," Dr. Wren said at the press briefing. "With a bit more research, we'll be able to choose specific bacteria to potentially readjust the balance of the microflora [in humans] when it's been disturbed. So this is very important for C. difficile infection, but I also think that, as a general principle, bacteriotherapy may be important in other chronic conditions such as ulcerative colitis and Crohn's disease, which are diseases that are also due to an imbalance of the gut microflora."

Posted by Tim Sandle

Sunday 22 September 2013

Antibiotic-Resistant Staph Infections reduce in U.S.

Methicillin-resistant Staphylococcus aureus (MRSA) infections occur most frequently among persons in hospitals and healthcare facilities, including nursing homes, and dialysis centers.

The number of "invasive" MRSA cases severe infections that typically require hospitalization, and can be fatal has declined significantly in the United States. In 2011, there were more than 30,000 fewer invasive cases than in 2005, the study shows. That's a 31 percent reduction in the rate of infection (per 100,000 people).

The drop was seen primarily in MRSA infections acquired at hospitals and nursing homes, where most cases are picked up, said Dr. Raymund Dantes, a physician and researcher at Emory University in Atlanta. These cases are called health-care-associated MRSA, and often involve pneumonia and infections of the bloodstream and surgical sites, according to the Centers for Disease Control and Prevention (CDC).

The number of community-associated MRSA cases has declined by 5 percent since 2005, according to a published in the journal JAMA Internal Medicine ("National Burden of Invasive Methicillin-ResistantStaphylococcus aureus Infections, United States, 2011"). The number of deaths associated with MRSA has also dropped. In 2005, more than 21,000 people in the U.S. were infected with MRSA at the time of their death, Dantes said. By 2011, the number had fallen to slightly more than 11,000 a 47 percent drop.

Posted by Tim Sandle

Saturday 21 September 2013

What Are Prions?

What Are Prions?

Tim Sandle
By Tim Sandle, Ph.D, M.A., BSc (Hons), CBiol, MSBiol., MIScT
A prion is short-hand for proteinaceous infectious particle. Prions are infectious proteins thought to cause disease as viruses do (prions are misfolded, misshapen, proteins). The key difference between a prion and a virus is that prions lack the DNA or RNA that forms the command structure of a virus. Prions have been implicated with a number of diseases, including scrapie, kuru (once called laughing sickness), Creutzfeldt-Jakob disease, and in Bovine Spongiform Encephalopathy (BSE) (the so-termed Mad Cow Disease). Mad-cow disease involves prions which have been passed between cattle by eating feed containing (or contaminated with) brain matter from infected animals, and can then be passed on to humans who eat the similarly contaminated meat of infected cattle. There was an outbreak of this disease in British cattle in the 1980s.
The prion proteins contradict a central tenet of molecular biology: that genes affect proteins, but proteins do not affect DNA. To date, any known disease transmitted by prion is untreatable. Prions attack the nervous system, particularly the brain. Once in an animal's brain cells, proteins near the prions apparently begin to deform and refold themselves to match the defective prion. In sheep, scrapie-infected animals stagger and die as their brains disintegrate. With BSE, humans suffer a hideously similar fate.

Posted by Tim Sandle

U.S. Antibiotic Resistance Threat

The U.S. CDC estimates that at least 23,000 people in the U.S. die each year as a result of antibiotic-resistant infections.
Furthermore, the U.S. Center for Disease Control and Prevention (CDC) estimates that over 2 million people become infected with antibiotic-resistant bacteria each year. This is the first federal estimate of antibiotic-resistant infections and comes from a new report.
The introduction to the CDC report discusses the spread of antibiotic resistant bacteria: "Antibiotic-resistant infections can happen anywhere. Data show that most happen in the general community; however, most deaths related to antibiotic resistance happen in healthcare settings such as hospitals and nursing homes."
The alarming figures highlight the growing spread of antibiotic resistant bacteria. This includes antibiotic-resistant bacteria being isolated in specific spots along the Hudson river, from the Tappan Zee Bridge to lower Manhattan. The cause is linked to raw sewage being pumped into the water, as the Digital Journal reported.
One concern is with the over prescribing of antibiotics. The issue here is that such ‘free use’ of antibiotics leads to more antibiotic resistant microorganisms in the community. The risks posed by bacteria resistant to the common antibiotics used is a significant global health issue. Another area of importance is the antibiotic use in animals, which the CDC report considers to be unnecessary and inappropriate.
The microorganisms considered to be of the greatest threat are: Clostridium difficile, Carbapenem-resistant Enterobacteriaceae and Drug-resistant Neisseria gonorrhoeae. The reports also lists 12 other microorganisms, including drug-resistant tuberculosis and methicillin-resistant Staphylococcus aureus (MRSA), as “serious” threats, and another three others “concerning.”
Commenting on the CDC report, Tufts University microbiologist Stuart Levy told The New York Times: "They have come up with hard numbers where it has been only guesswork. This sets a baseline we can all believe in."
The CDC report recommends four core actions that will help fight the deadly infections:
preventing infections and preventing the spread of resistance, tracking resistant bacteria, improving the use of today’s antibiotics, promoting the development of new antibiotics and developing new diagnostic."
The report summarizes the issues of concern and the importance of developing a strategy : "Bacteria will inevitably find ways of resisting the antibiotics we develop, which is why aggressive action is needed now to keep new resistance from developing and to prevent the resistance that already exists from spreading."

Posted by Tim Sandle

Friday 20 September 2013

Ten Rules of Good Manufacturing Practice

Ten Rules of Good Manufacturing Practice

By Tim Sandle

Good Manufacturing Practice (GMP) refers to the rules governing the manufacture of a safe and efficacious pharmaceutical product.  There are two main global bodies that oversee GMP. These are the U.S. Food and Drug Administration (FDA), where manufacturers are governed by the Code of Federal Regulations (CFRs), in particular 21 CFR 210 – 211, and the European Union (EU GMP), which is overseen by the European Medicines Agency.

These different agencies control the production of medicines through various licences, such as:
  • Manufacturers licence
  • Manufacturers Specials licence
  • Marketing Authorisation licence
  • Wholesale Dealers licence
  • Investigational Medicinal Products (IMP) licence
Compliance with these licences is assessed routinely through GMP inspections, which are normally conducted every two years. Regulators aim to assess whether the pharmaceutical company is manufacturing the product in the way that is stated in licences, policies, procedures and other official documentatin.
Not all aspects of GMP are written down in regulations, such as innovations relating to the latest technologies. This part of GMP is called ‘current’ or cGMP. It is up to each pharmaceutical organisation to be familiar with the current ‘hot topics’.

Key aspects of GMP compliance 

There are many important parts of GMP compliance. Of these, the most critical are:
Proper documentation and records - 'if it is not recorded it never happened' according to the inspectors. It is important that all actions, events and decisions relating to the quality of the product must be recorded at the appropriate level of detail in a controlled way.

  • Control of materials. This refers to ensuring that all materials used, whether they be the raw materials, components such as bottles or stoppers, and packaging materials, are of the sufficient quality and are traceable.
  • Thorough housekeeping and cleaning. GMP requires that people work in an orderly and methodical way and that work areas are neat, tidy and there is segregation between tasks where required. This will reduce the potential for errors and mix-ups to occur
  • Responsible personnel behaviour. This includes such areas as reporting incidents and errors immediately, behaving appropriately in controlled areas (e.g. minimising particles and microbial contamination in cleanrooms)
  • Process control at all steps. This level of control relates to ensuring that all parameters are in control throughout the manufacturing process (e.g. time, temperature, pH) and reporting immediately if there is a noticeable drift or adverse trend.
  •  Maintenance of equipment. This involves ensuring all equipment used in the manufacture of product is 'fit for purpose' and is cleaned, maintained, calibrated and verified as appropriate and labelled / recorded as such. This is supported through initial and on-going validation. Any equipment not fit for purpose should ideally be removed or clearly labelled.
Ten Rules of Good Manufacturing Practice 

To support the key aspects of GMP outlined above and for the essential elements to be conveyed to personnel in a way that is easy to understand but at the same time does not dilute down what is essential, drawing up a set of rules can make for a useful training aid.

GMP requires that initial and on-going training is provided for all personnel whose duties take them into production areas or into controlled laboratories (including the technical, maintenance and cleaning personnel), and for other personnel whose activities could affect the quality of the product.
This includes:
  • Basic training on the theory and practice of GMP (the reason why you are doing this refresher),
  • Training on specific duties assigned to them (e.g. against SOPs and other controlled instructions).
Ten suitable GMP ‘rules’, to be used for staff training or to act as a reminder, are set out below. 
  1. Confirm you are trained and have correct written instructions before starting any job
  2.  Follow instructions exactly
  3.  Report errors and bad practices immediately
  4.  Ensure you have the right materials before you start a job
  5.  Use the correct equipment for the job, confirm its status and cleanliness
  6. Maintain good segregation. Protect against contamination
  7. Work accurately, precisely and methodically
  8. Maintain good standards of cleanliness and tidiness
  9. Ensure changes are pre-approved (through the change control system)
  10.  Do not make assumptions - check it out


This article has set out a basic introduction to GMP and has considered the key points and how these can be effectively communicated to staff. The main learning point is that a lot of problems and errors can be avoided by preparing thoroughly before starting a task and from reading instructions beforehand.

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 Posted by Tim Sandle

Thursday 19 September 2013

Cleanroom Particle Counting: The 5 Micron Issue

Cleanroom Particle Counting: The 5 Micron Issue

Tim Sandle
The IEST Journal has an interesting article on cleanroom metrology by Lothar GaiThe article explores the 5 micron particle size issue. As those involved with cleanrooms will know there are two particle count sizes looked for within cleanrooms: 0.5 and 5.0 micron.
The FDA emphasize in the Guide to Aseptic Filling that the 0.5 micron size is the important one for determining if the environment is below or above the accepted level of particles and in doing so draws upon the ISO 14644 cleanroom standard. However, more controversially with Europe, the EU GMP Guide states that both particle sizes are important.
In arguing against the need to measure 5.0 microns, Gail states:

EC GMP requiring the detection of 5-µm particles with a sample volume of at least 1 m³ for ISO Class 5 classification and monitoring, overlooks some essential facts:
  • 5-µm particle counts in an ISO Class 5 environment should be avoided in principle due to background noise level and poor resolution. The poor reliability of 5-µm particle counts cannot be fully compensated by increasing the measuring time.
  • 5-µm particle determination proves to be about 10 times more expensive and timeconsuming than 0.5-µm particle counts.
  • Currently there is no scientific evidence that 5-µm particle detection offers any improvement for cleanroom hygiene control. EC GMP regulation impedes international harmonization of cleanroom qualification and monitoring procedures.
Even with the latest development of particle counters that offer substantially higher sampling flow rates, the situation does not improve: Areas of ISO Class 5 normally are as small as possible. A particle counter with high sample flow rates cannot be placed in that area since the high sample flow is withdrawn from a small volume. In small areas such as pass-throughs, when the sample flow air is returned into the environment, the pressure differential may be affected; when the sample flow air is returned into the measured area, the air change rate may be affected.
The article can be found here: IEST cleanrooms

Posted by Tim Sandle

Wednesday 18 September 2013

Latest Pharmig publications

Latest Pharmig publications - for the microbiologist's book shelf. Pharmig is the UK / Ireland Pharmaceutical Microbiology Interest Group.

See: Pharmig or see the poster below.
Posted by Tim Sandle

Quality Management Systems

Quality Management Systems

Tim Sandle
By Tim Sandle, Ph.D, M.A., BSc (Hons), CBiol, MSBiol., MIScT
The objectives of a Quality Management System are to:
  • Set direction and meet customers' expectations
  • Improve process control
  • Reduce wastage
  • Lower costs
  • Increase market share
  • Facilitate training
  • Involve staff
  • Raise morale
The basis of a Quality Management System is set out in: ISO/FDIS 9001:2000 — Quality management systems — Requirements.
The adoption of a QMS needs to be a strategic decision of an organisation, and is influenced by varying needs, objectives, the products/services provided, the processes employed and the size and structure of the organisation. A QMS must ensure that the products/services conform to customer needs and expectations, and the objectives of the organisation. Issues to be considered when setting up a QMS include:
  • Design and build includes the structure of the quality management system, the process and its
  • implementation. It's design must be led by senior managers to suit the needs of the organisation, and this is ideally done using a framework to lead the thinking. Design of the QMS should come from determining the organisation's core processes and well-defined goals and strategies, and be linked to the needs of one or more stakeholders. The process for designing and building the QMS must also be clear, with the quality function playing a key role, but involvement and buy-in to the system must also come from all other functions.
  • Deployment and implementation is best achieved using process packages, where each core process is broken down into sub-processes, and described by a combination of documentation, education, training, tools, systems and metrics. Electronic deployment via Intranets is increasingly being used.
  • Control of the QMS will depend on the size and complexity of the organisation. ISO is a site-based system, and local audits and reviews are essential even if these are supplemented by central reviews.
  • Local control, where possible, is effective, and good practice is found where key stakeholders are documented within the process and where the process owner is allowed to control all of the process. Ideally, process owners/operators are involved in writing procedures.
  • Measurement is carried out to determine the effectiveness and efficiency of each process towards attaining its objectives. It should include the contribution of the QMS to the organisation's goals; this could be achieved by measuring the following:
    • Policy definition completeness
    • Coverage of business
    • Reflection of policies
    • Deployment
    • Usage
    • Whether staff find the QMS helpful in their work
    • Speed of change of the QMS
    • Relevance of QMS architecture to the job in hand
A form of scorecard deployed through the organisation down to individual objective level can be employed, and the setting of targets at all levels is vital.
Review of the effectiveness, efficiency and capability of a QMS is vital, and the outcome of these reviews should be communicated to all employees. Reviewing and monitoring should be conducted whether or not improvement activities have achieved their expected outcomes.
Improvement should follow as a result of the review process, with the aim of seeking internal best practice. It is part of the overall improvement activities and an integral part of managing change within the organisation.
An effective QMS must ensure that the organisation has a strong Customer Focus. Customer needs and expectations must be determined and converted into product requirements. Top management have to demonstrate Leadership. Providing unity of purpose through an appropriate quality policy, ensuring that measurable objectives are established, and demonstrating that they are fully committed to developing, sustaining and improving the QMS.
Managers must ensure that there is Involvement of People at all levels in the organisation. This includes ensuring that there is an awareness of the importance of meeting customer requirements and responsibilities in doing this, and people are competent, on the basis of appropriate training and experience.
An effective QMS must be a strategic tool designed to deliver business objectives, and must have, at its core, a Process Approach, with each process transforming one or more inputs to create an output of value to the customer. The key business processes may be supported by procedures and work instructions in those cases where it is judged necessary to rigidly define what rules are to be followed when undertaking a task. Most organisations will have core business processes that define those activities that directly add value to the product or service for the external customer, and supporting processes that are required to maintain the effectiveness of the core processes.

The understanding of the many interrelationships between these processes demands that a Systems Approach to management is adopted. The processes must be thoroughly understood and managed so that the most efficient use is made of available resources, to ensure that the needs of all the stakeholders — customers, employees, shareholders and the community — are met.
Customer satisfaction is a constantly moving entity depending on changes in technology and the market place, so an effective QMS must be in a state of Continual Improvement. For this to be achieved, attention needs to be given to both the voice of the customer - through complaint analysis, opinion surveys and regular contacts – and the voice of the processes – through measurement, monitoring and analysis of both process and product data. This will result in Factual Decision Making.
Each organisation is itself only a link in the chain of a larger raw material process, and for the long term needs of the community and the organisation there needs to be Mutually Beneficial Supplier Relationships.
Audits, reviews and assessments

A good QMS will not function or improve without adequate audits and reviews. Audits are carried out to ensure that actual methods are adhering to the documented procedures, whilst system reviews should be carried out periodically and systematically, to ensure the system achieves the required effect.
There should be a schedule for carrying out audits, with different activities possibly requiring different frequencies. An audit should not be conducted just with the aim of revealing defects or irregularities – they are for establishing the facts rather than finding faults. Audits do indicate necessary improvement and corrective actions, but must also determine if processes are effective and that responsibilities have been correctly assigned. The emphasis on process improvement and enhancing customer satisfaction in the revised standard will require a more thoughtful approach to auditing.
The generic steps involved in an audit are:
  • Initiation
    • Scope
    • Frequency
  • Preparation
    • Review of documentation
    • The programme
  • Working documents
    • Execution
  • Opening meeting
    • Examination and evaluation
    • Collecting evidence
    • Observations
  • Close the meeting with the auditee
  • Report
    • Preparation
    • Content
    • Distribution
    • Completion
    • Report
    • Submission
    • Retention
A quality management system review should take place, possibly once a year, which should cover:
  • Results of audits
  • Customer feedback
  • Process and product conformity
  • Status of preventative and corrective actions
  • Follow up actions from previous management reviews
  • Changes that could effect the QMS
  • Recommendations for improvements
  • Outputs should include:
  • Improvements to the QMS and processes
  • Improvements of a product related to customer requirements
  • Resource needs
In addition, the procedures for conducting audits and reviews and the results from them should be documented, and also be subject to review. Internal system audits and reviews should be positive and conducted as part of the preventative strategy, and not as a matter of expediency resulting from problems. The assessment of a quality system against a standard or set of requirements by internal audit and review is known as a first-party assessment or approval scheme. If an external customer makes the assessment of a supplier, against either its own, or a national or international, standard, a second-party scheme is in operation. The assessment by an independent organisation, not connected with any contract between the customer and supplier, but acceptable to them both, is an independent third-party assessment scheme.
All managers, not just the staff in the "quality department", need to be fully committed to operating an effective quality management system for all the people within the organisation. The system must be planned to be effective and achieve its objectives in an uncomplicated way. It should also not be static, but be flexible, to enable constant seeking of improvements
Quality Management Review

The object of the Quality Management Review is to provide an overview of the results from the Quality Control and Quality Assurance functions. The review forms part of an organization's Quality Management Systems (as detailed in ISO 9001). The issues covered will vary between different workplaces. However, issues often included issues are results of audits; discussions of follow up items; a review of progress relating to non-compliances and discussions relating to the effectiveness of corrective and preventative action; test and sampling efficiency times; customer complaints; rejects; out of specification results from test data; microbiological contamination issues and trends in relation to processing of product and to the manufacturing environment. Issues of major concern are often considered using risk management techniques.
Data is presented by participants from different departments. The data is normally measured against a target (to allow for effectiveness, efficiency and capability to be measured). This can be relatively straightforward, such as the number of internal audits completed against a target level (such as 95% of audits to be completed to schedule) or more complex when relating to statistical process control charts for laboratory test data.
Participants will include representatives of laboratories, production, process, pharmacy and ward management. Meetings are held either monthly, quarterly or annually (at my workplace, the meetings are held quarterly).
Where problems or upward trends are identified the aim of the meeting is to identify the risk, assign a priority, to agree actions and to track progress. For issues that cannot be satisfactorily dealt with these are referred to senior management. Quality Management Review meetings may sometimes elect to form subgroups to examine specific areas, such as sampling; new processes technologies and so on.
It is important that the outcomes of the Quality Management Review are communicated to all members of staff.

Posted by Tim Sandle

Tuesday 17 September 2013

What Is The Gram stain?

What Is The Gram stain?

Tim Sandle
By Tim Sandle
The primary staining technique used to differentiate bacteria is the Gram stain. The Gram stain method employed includes the four-step technique: Crystal violet (primary stain); iodine (mordant); alcohol (decolorizer); safranin (counter stain) or the three-step method in which the decolorization and counter-staining step are combined. Done correctly, Gram-positive organisms retain the crystal violet stain and appear blue; Gram negative organisms lose the crystal violet stain and contain only the counter-stain safranin and thus appear red. Common pitfalls in this method are that heat fixation may cause Gram-positive cells to stain Gram-negative and older cultures may give Gram-variable reaction; using too much decolorizer could result in a false Gram-negative result and not using enough decolorizer may yield a false Gram-positive result.
The Gram reaction is based on the differences in the cell wall composition for the two cellular ‘groups'. The bacteria that retained the stain (the Gram-positive bacteria) have a higher peptidoglycan and lower lipid content than those that do not retain the stain (the Gram-negative bacteria). The effect of the solvent is to dissolve the lipid layer in the cell wall of the Gram-negative bacteria, thereby causing the crystal violet to leach out; whereas for Gram-positive bacteria the solvent dehydrates the thicker cell walls, blocking any diffusion of the violet-iodine complex, which closes the pores of the cell and retains the stain. There are now several automated Gram stain devices available on the market that can reduce the labour requirement required when performing several multiple Gram stains and, possibly, improve accuracy.
In addition to the difference based on cell wall, microscopic examination of the stains allows the cellular shape to be determined. Bacteria commonly fall into the categories of coccus (spherical), rod, vibrio (curved), spirilla (spiral) and plemomorphic (variable).

Monday 16 September 2013

EMA Concept paper on bioequivalence

The European Medicines Agency (EMA) have issued a concept paper on ‘Development of product-specific guidance on demonstration of bioequivalence’.

According to the EMA: “Bioequivalence studies are conducted, amongst others, as part of the development of generic medicines to demonstrate that they are bioequivalent to the reference medicine. The aim of developing product-specific guidance is to enable a consistent approach to the assessment of applications based on bioequivalence data across all submission routes, i.e. the centralised, decentralised, mutual-recognition and national procedures. The guidance is intended to help companies design study programmes that meet the expectations of European Union regulators, allowing for better transparency and predictability of the scientific assessment during the authorisation process.”

For further details see: EMA

Posted by Tim Sandle

Sunday 15 September 2013

How quickly can E.coli grow?

MIT physicist Jeremy England mathematically has modeled the replication of E. coli bacteria and found that the process is nearly as efficient as possible: E. coli produce at most only about six times more heat than they need to meet the constraints of the second law of thermodynamics.

He focused on the biological process of cell division, through which one cell becomes two. During the 20-minute replication process, a bacterium consumes a great deal of food, rearranges many of its molecules -- including DNA and proteins -- and then splits into two cells. One of the common reactions that occur during replication is formation of new peptide bonds, which form the backbone of proteins.

The finding suggests that bacteria could grow dramatically faster than they do now and still obey the second law of thermodynamics. England says that because cell replication is just one of the many tasks E. coli need to perform, it's unlikely they would evolve to their most efficient possible growth rate. However, for synthetic biology applications, it may be useful to create bacteria that can divide faster, which this paper shows is theoretically possible.

The findings have been published in the Journal of Chemical Physics, for further details see:

Jeremy L. England. Statistical physics of self-replication. The Journal of Chemical Physics, 2013; 139 (12): 121923 DOI: 10.1063/1.4818538

Posted by Tim Sandle

Saturday 14 September 2013

The journey of marine microbes

By collecting water samples up to six kilometres below the surface of the Southern Ocean, UNSW researchers have shown the impact of ocean currents on the distribution and abundance of marine microorganisms.

Twenty five samples were collected across a 3000 kilometre stretch of ocean between Antarctica and the southern tip of Western Australia. Sampling depths were determined by temperature, salinity and dissolved oxygen measurements, to ensure microbes were collected from all the distinct water masses of the Southern Ocean.

These water masses include the circumpolar deep water, which flows toward the south pole from the Indian, Pacific Ocean and Atlantic oceans; the surface water near the Antarctic coastline; and the cold, dense Antarctic bottom water, which flows north, away from the pole, at more than 4 kilometres depth.

Genetic sequencing of the microbial DNA in each sample was carried out to characterise the microbial communities in different water-masses. The research shows that communities that are connected by ocean currents are more similar to each other.

For more details, see the following paper:

David Wilkins, Erik van Sebille, Stephen R. Rintoul, Federico M. Lauro, Ricardo Cavicchioli. Advection shapes Southern Ocean microbial assemblages independent of distance and environment effects. Nature Communications, 2013; 4 DOI: 10.1038/ncomms3457

Posted by Tim Sandle

EU GMP update

A new version of chapter 2 of the EU GMP guide ('Personnel') has been published by the European Commission (16th August 2013). The chapter is effective as of February 2014, according to the ECA.

The new chapter incorporates ICH Q10 'Pharmaceutical Quality System'.

The revised chapter describes the roles and responsibilities of senior management, the need to ensure that consultants are suitably qualified, the key aspects of a quality management system, and there is the addition of the position 'Head of Quality Assurance' for the first time.

The revised chapter can be found here: GMP 2

Posted by Tim Sandle

Friday 13 September 2013

House bill gives FDA new power over compound pharmacies

Regular readers will know about the current issues with many U.S. compounding pharmacies (see for example the Digital Journal). Many of these issues have related to sterility assurance.

Pharmaceutical Microbiology has run a series of investigative articles on the crisis facing U.S. compounding pharmacies as the U.S. Food and Drug Administration (FDA) embarks on a series of inspections into issues of quality and sterility of medicines.
These different events, in short time frame, suggest that the continuing problems with quality control in certain U.S. pharmacies continues to be an issue of major concern, especially in relation to the potential risks of microbiological contamination.

In light of this, the news has come in that U.S. lawmakers are introducing a bill that would give drug regulators more authority over compounding facilities. 'The Compounding Clarity Act', introduced on September 12, 2013, by Reps. Gene Green (D-Texas), Morgan Griffith (R-Va.) and Diana DeGette (D-Colo.), would give the Food and Drug Administration (FDA) power to oversee major drug manufacturing facilities.

The legislation comes nearly a year after an outbreak of fungal meningitis, during which 64 people were killed. Those deaths have been blamed on contaminated drugs from a Massachusetts facility (the New England Compounding Center). 

The legislation expands the authority of the FDA to oversee large compounding pharmacies, which alter strength, dosage and ingredients of drugs to make customized batches of medication. Large facilities like the one at the root of the 2012 outbreak are largely exempt from FDA oversight under current law. The bill also calls for a new notification system to make sure that the FDA acts on complaints it receives from state pharmacy boards. However, only large compounding pharmacies would be subject to the new restrictions, not traditional facilities.

For further details, see this letter from the NPCA.

Posted by Tim Sandle

Antimicrobial strategy 2013- 2018

The British government has unveiled a five-year antimicrobial strategy. This forms part of a multi-pronged global approach to address the growing spread of antimicrobial resistance.

The objective is to find more efficient means to develop new antimicrobials. While resistance to existing antibiotics is snowballing, the stream of antibiotics coming through R&D pipelines is drying up fast; a 75% drop in the number of systemic antibacterials approved by US regulators was seen between 1983 and 2007, with a further drop observed in subsequent years.

The five-year antimicrobial resistance strategy outlines that steps are being taken to:

Improve how we prevent and manage infections in people and in animals; including through better hygiene and monitoring of bacteria in medical and community settings, and through better farming practices.

Improve education and training around the prescribing of antibiotics to reduce inappropriate usage and make sure patients get the right antibiotics, at the right time and for the right duration.

Collect better data on the resistance of bugs so we can track them more effectively, find the most resistant bacteria and step in earlier where there is resistance to antibiotics.

Provide funding of up to £4million to set up a new National Institute of Health Research (NIHR) Health Protection Research Unit which will focus on AMR and healthcare associated infections. In recognition of the importance of quick action, the NIHR is also running a themed research call to encourage AMR research across a range of areas.

Explore ways to encourage the development of new antibiotics, rapid diagnostics and other treatments by working with industry and across Government.

One part of the strategy is work with commercial pharma to develop new antimicrobials for the market. A report by Office of Health Economics suggests considering the use of incentives such advance market commitments, priority review vouchers, patent extensions, and direct R&D funding to help fuel activity in the area.

For more details, see: UK antimicrobial

Posted by Tim Sandle

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