Sunday, 23 November 2014

Real-time tracking system developed to monitor dangerous bacteria

Combining a PET scanner with a new chemical tracer that selectively tags specific types of bacteria, researchers working with mice report they have devised a way to detect and monitor in real time infections with pathogenic Gram-negative bacteria.

The new model emerged from a combination of existing PET scan technology -- a sophisticated 3-D visualization system for tumor imaging -- with an ingredient commonly used in sugar-free foods known as sorbitol. The model capitalizes on Gram-negative bacteria's fondness for sorbitol, which they readily soak up. By contrast, other classes of bacteria and other microorganisms, cancer, and human cells do not absorb sorbitol. The researchers hypothesized that converting an already available PET imaging tracer into radio-labeled sorbitol would selectively tag and light up clusters of Gram-negative bacteria inside the body.

For further details, see:

Edward A. Weinstein, Alvaro A. Ordonez, Vincent P. Demarco, Allison M. Murawski, Supriya Pokkali, Elizabeth M. Macdonald, Mariah Klunk, Ronnie C. Mease, Martin G. Pomper, and Sanjay K. Jain. Imaging Enterobacteriaceae infection in vivo with 18F-fluorodeoxysorbitol positron emission tomography. Science Translational Medicine, October 2014 DOI: 10.1126/scitranslmed.3009815

Posted by Tim Sandle

Saturday, 22 November 2014

USP 2014, 2nd supplement

With: United States Pharmacopiea and National Formulary, 2nd Supplement to USP37-NF32. Official 01 Dec 2014, there are some items of interest:

a)      General Chapters

Listed are items in which changes have been made to existing official text:

Physical Tests and Determinations

Chapter 791 pH

Chapter 1196 Pharmacopeial Harmonization

Chapter 1229.6 Liquid Phase Sterilization

Chapter 1240  Virus Testing of Human Plasma for Further Manufacture [NEW]

b)      USP and NF Excipients

Updates to the following

  • Polysorbate 80: Identification – Test A and Infrared Absorption, Test B (added), Assay – Composition of Fatty Acids, Impurities – Heavy Metals, Method II, Specific Tests – Specific Gravity and Viscosity – Capillary Viscometer Methods or Rotational Rheometer Methods, Additional Requirements - USP Reference Standards.
  • Cupric Sulfate: Specific Tests – Loss on Drying, Additional Requirements – Labelling (added)

Posted by Tim Sandle

Friday, 21 November 2014

Endotoxin testing – European Pharmacopeia changes

A proposal has been made to amend the European Pharmacopeia chapter on guidance for the bacterial endotoxin test – chapter 5.1.10.

The proposed changes are:

In the context of the new bacterial endotoxins Ph. Eur. policy, a new section (2-4) includes aspects to be considered when establishing an endotoxin limit for a specific substance or product; also, reference is made to the fact that an endotoxin limit is not always provided in a specific monograph.

– Reference is made to general chapter 2.6.30. Monocyte-activation test as an alternative to the rabbit pyrogen test, and a recommendation is given to perform a risk assessment when using the bacterial endotoxin test as a pyrogenicity test, due to the potential for contamination by non-endotoxin pyrogens. In this respect, the previous section 11 concerning the replacement of the rabbit pyrogen test by a test for bacterial endotoxins is substituted with a new text in agreement with a strategy to be applied for testing of bacterial endotoxins or non-endotoxin pyrogens. A distinction is made between replacement methods already described in the Ph. Eur. and other alternative methods.

– In the context of the 3R’s, a test for bacterial endotoxins or a monocyte-activation test is preferred to the rabbit pyrogen test. Therefore, implementation of the rabbit pyrogen test has to be justified and authorised and is appropriate only when the bacterial endotoxin test or the monocyte-activation test cannot be validated.

– Reference is made to the use of alternative reagents to the Limulus amoebocyte lysate, such as recombinant factor C: this practice avoids the use of endangered animal species and can be considered in the context of the use of an alternative method as described in the General Notices.

A number of additional specific revisions have been made.

– In line with current knowledge, Method A is no longer declared as the reference method, and all methods A to F of general chapter 2.6.14. Bacterial endotoxins can be used. Where the method is stated in the monograph, the use of another method must be supported by evidence of validation.

–The expression ‘threshold endotoxin concentration’ has been replaced by the more appropriate expression ‘endotoxin limit concentration’ to harmonise with general chapter 2.6.30. Monocyte-activation test.

– A new entry has been included in Table 5.1.10.-1 for formulations administered per square metre of body surface.

Finally, the structure of the general chapter has been modified to improve its clarity.

The proposal has been added to Pharmeuropa 26.4.

Posted by Tim Sandle

Thursday, 20 November 2014

Pharmig News #57

A new edition of Pharmig News has been published. The current issue features:
  • An article by Tony Cundell on bioburden control of non-sterile drug substances and products, based on a critique of the new USP chapter 1115
  • A review article, presenting research on Streptococcus anginas, by Antonella Chesca from the Transilvania University in Romania
  • The regular update on standards, monographs and articles on interest, by Tim Sandle.

Copies have been sent to Pharmig members. If you are interested in reading a copy, please contact the Pharmig office.

Posted by Tim Sandle

Wednesday, 19 November 2014

Medicines and the Microbiome

We now know more than ever before about the complex ecosystem of bacteria, fungi, and viruses within our bodies. How can that knowledge be best applied in drug development and manufacturing?

This is the basis of a short opinion piece written by Tim Sandle for a new magazine called The Medicine Maker.

The issue can be accessed here.

The reference is:

Sandle, T. (2014) Medicines and the Microbiome, The Medicine Maker, Issue 1, p18

Tuesday, 18 November 2014

Exclusion of Objectionable Microorganisms

The PDA has issued a new publication of interest:

PDA Technical Report No. 67 'Exclusion of Objectionable Microorganisms from Nonsterile Pharmaceuticals, Medical Devices, and Cosmetics'.

The purpose of the publication is:

“The purpose of this technical report is to provide guidance to the nonsterile producmanufacturing industry on how to manage the microbial risks associated with manufacturing and storage and how to determine what isolates would be deemed an objectionable microorganism in nonsterile products that is in alignment with the microbial limits requirements for releasing these products into the marketplace. Nonsterile products exceeding the microbial count limit and/or containing specified microorganisms for their product type would be expected to be rejected. Specified microorganisms include microorganisms with compendial requirements to be absent in a particular dosage form, and/or required by a national board of health to be excluded from a registered non-sterile product. The contamination of marketed products by potentially objectionable microorganisms continues to be an infrequent but chronic problem. A U.S. survey of reported microbiologically related recalls between 2004 and 2011 found that 72% of recalls of nonsterile products were associated with objectionable microorganisms rather than exceeding microbial enumeration limits (1). Of the 144 recalls for nonsterile products, 5% involved nonsterile pharmaceutical drug products, 42% were for OTC drug products, 31% were for cosmetics, 14% were for medical devices and 8% were for dietary supplements. The average rate of reported recalls is 20 per year.”

For details see: PDA

Posted by Tim Sandle

Monday, 17 November 2014

Pyrogen testing – European Pharmacopeia

The Ph. Eur. is proposing an amendment for the pyrogen test monograph (2.6.8). The only change is in directing users to consider using an alternative to the rabbit model.

The change states:

“In accordance with the provisions of the European Convention for the Protection of Vertebrate Animals used for Experimental and Other Scientific Purposes, tests must be carried out in such a way as to use the minimum number of animals and to cause the least pain, suffering, distress or lasting harm. Wherever possible and after product-specific validation, the pyrogen test is replaced by the monocyte-activation test (2.6.30).”

Interestingly, the recommendation is towards the MAT rather than LAL testing.

The proposal has been added to Pharmeuropa 26.4.

 Posted by Tim Sandle

Fungicidal activity of biocides against fungal isolates

A new paper of interest has been published: “In vitro fungicidal activity of biocides against pharmaceutical environmental fungal isolates”.

The paper has been written by T. Sandle, R. Vijayakumar, M. Saleh Al Aboody and S. Saravanakumar and it has been published in the Journal of Applied Microbiology.

The abstract states:

Aims: To determine the minimum inhibitory concentrations (MIC) of a range of cleanroom fungi against three disinfectants common to the pharmaceutical and healthcare sectors: biguanide (chlorhexidine) and two quaternary ammonium compounds (benzalkonium chloride and cetrimide).
Methods and Results: The in vitro fungicidal activities of the three biocides were studied against 112 cleanroom fungal isolates using broth microdilution technique (CLSI M38-A2 standard).
Conclusions: Minimum inhibitory concentration (MIC) for all three biocides against hyaline fungi showed results of not more than 16 lg ml-1. Alternaria showed <32 lg ml-1 and other dematiaceous fungi reported that 8–16 lg ml-1 for biguanides and QACs. This study clearly demonstrates that the most frequently isolated micro-organisms from an environmental monitoring programme may be periodically subjected to broth microdilution testing with cleanroom disinfectant agents used in the disinfection programme confirm their sensitivity profile.
Significance and Impact of the Study: No large collection of data exists on the activity of biocides on pharmaceutical cleanroom fungal isolates. This is the first study report with large collection of cleanroom fungal isolates tested against common biocides using the broth microdilution antifungal susceptibility testing to determine the MIC value. The data presented support a quality control procedure for cleanroom disinfection.

The reference is:

Sandle, T., Vijayakumar, R., Saleh Al Aboody, M. and Saravanakumar, S. (2014) In vitro fungicidal activity of biocides against pharmaceutical environmental fungal isolates, Journal of Applied Microbiology, 117 (5): 1267 – 1273

For further details, please contact Tim Sandle

Posted by Tim Sandle

Sunday, 16 November 2014

Fighting a pathogen with gut microbes

Clostridium difficile infections can be prevented through the rebalancing of bile acids in the gut by introducing certain commensal microbes, according to a study published in Nature. Eric Pamer of the Memorial Sloan Kettering Cancer Center in New York City and his colleagues have demonstrated the efficacy of this approach in both mice and humans.

While antibiotics work wonders fighting myriad infections, they can also wipe out the large contingent of beneficial bacteria that populate the human gut. Such widespread, indiscriminate destruction paves the way for infectious pathogens, including C. difficile—which can cause extreme diarrhea, abdominal pain, and if left untreated, even death.

The researchers sequenced the gut microbiomes of both mice and humans in search of individual species capable of eradicating infection. They discovered that in antibiotic-treated mice, CDI resistance was strongly correlated with the abundances of C. scindens and, to a lesser extent, 10 other bacterial taxa. A similar exploration of the intestinal microbiota of human patients undergoing a stem-cell transplantation procedure that left them vulnerable to CDI also pointed to C. scindens as the most potent source of infection resistance.

Administering C. scindens to antibiotic-treated mice infected with C. difficile resulted in significantly increased survival rates—80 percent, versus 50 percent for a control substance. A cocktail of C. scindens plus three other C. difficile-inhibiting bacteria was even more effective, resulting in 100 percent survival. In addition, the abundance of both C. scindens and the bacterial cocktail were strongly correlated with resistance.

Next, Pamer’s group investigated the mechanism underlying C. scindens-mediated inhibition of infection, focusing on the ability of the microbe to express the enzyme 7a-hydroxysteroid dehydrogenase. This enzyme, rare among intestinal bacteria, is critical for converting primary bile acids to secondary bile acids in the colon. C. difficile spores interpret the presence of primary bile acids as a signal that they are in the gut and should start germinating. The researchers hypothesized that C. scindens may prevent C. difficile growth by blocking this signal. To confirm this hypothesis, they loaded Petri dishes with the intestinal contents of antibiotic-exposed mice. As expected, C. scindens inhibited C. difficile. But when they added a chemical that binds bile acids, C. difficile flourished, suggesting that C. scindens-mediated inhibition of C. difficile is dependent upon modifying endogenous bile acids.
For further details, see the following paper published in Nature: "Precision microbiome reconstitution restores bile acid mediated resistance to Clostridium difficile."

Saturday, 15 November 2014

Archaeal origins and bacterial gene acquisitions

A phylogenetic analysis of more than 25,000 archaeal gene families found that the integration of bacterial genes into the genome paralleled the pattern of archaeal-specific genes in each of 13 orders of archaea, suggesting that archaeal lineages picked up groups of bacterial genes at the time of their formation.

About a third of the archaeal genes analyzed had homologs among bacterial genomes, and the phylogenies of these apparent genetic imports closely mirrored those of archaeal-specific genes in each of 13 orders of archaea, suggesting that the birth of each order coincided with the gene acquisitions.

The phylogenies revealed that 83 percent of the bacterial introductions occurred in methanogenic archaea, which are thought by some to be the most ancient groups of archaea and have a simple metabolism—anaerobic reduction of carbon dioxide to methane in the presence of hydrogen gas.

The conclusion that archaeal lineages abruptly picked up large groups of bacterial genes at the time of their formation, though supported by statistical tests, will require further analysis.

For further information, see Nature "Origins of major archaeal clades correspond to gene acquisitions from bacteria."

 Posted by Tim Sandle
(Reference: The Scientist)

Friday, 14 November 2014

European Pharmacopeia: Preparation of sterile products

The European Pharmacopeia has put the following revised chapter out for public comment:


The chapter states:

Sterility is the absence of viable micro-organisms, as defined by a sterility assurance level of 10− 6. Sterility is a critical quality attribute for a wide variety of human and veterinary preparations, including but not restricted to:

  • Preparations administered to normally sterile areas of the body, such as parenteral and ophthalmic preparations, some irrigation and inhalation preparations, intramammary and intrauterine preparations;
  • Preparations applied to severely injured skin, such as semi-solid preparations for cutaneous
  • application;
  • Preparations that are supplied sterile in order to prolong the shelf life of the product.
With the revised chapter, the following revisions are proposed: 
  • In the introduction, the reference to GMP has been removed;
  • In the section Sterility assurance level, the reference to exponential inactivation has been removed as membrane filtration is not a first order process;
  • The sections on the different sterilisation processes, where appropriate, now have the same format: principle, equipment, sterilisation cycle, cycle effectiveness and routine control; where required, relevant information has been added;
  • Modern concepts for validation of steam sterilisation have been added;
  • A wider description of the equipment suitable for dry heat sterilisation has been provided;
  • In the section Ionising radiation sterilisation, the reference to European Notes for Guidance
  • has been removed;
  • In the section Gas sterilisation, two different types of agents are defined: alkylating agents and oxidising agents. The establishment of the cycle effectiveness has been described in more detail;
  • In the section Membrane filtration, the description of the microbial challenge test has been removed as it is proposed for inclusion in the revised chapter on biological indicators;
  • In the section Aseptic preparation, freeze-drying under aseptic conditions is added.

The proposed revision is published in Pharmeuropa which is the free online publication from the EDQM.

Posted by Tim Sandle

Thursday, 13 November 2014

ISO 14644 Part 1 update


As part of the ISO periodic review cycle, ISO 14644-1, Cleanrooms and associated controlled environments — Part 1: Classification of air cleanliness is being revised. ISO TC209 Working Group 01, an international team of subject matter experts, is planning to assess the existing ISO 14644 document and propose changes for enhancements.

After discussing with statisticians, the expert working group is recommending modifications to the classification method. It is also implementing the key elements of ISO 14644-3, Cleanrooms and associated controlled environments — Part 3: Test methods in an effort to improve the document and thus enhance credibility and resulting quality.

Changes in Classification Method

The present ISO 14644-1 document depends on an ad-hoc approach to ascertain the location and number of sampling areas for classifying cleanrooms. This method, however, is not built on statistical sampling technique and also does not consider any risk-based evaluation. At present, the working group is recommending a randomized sampling location selection technique, in tandem with a risk-assessed, fixed-location sampling technique.

Founded on the hypergeometric statistical model, the randomized sampling technique enhances confidence that the selected sample provides 95% assurance that the results represent 90% of all areas in the cleanroom. Examining the additional risk, the fixed sampling location technique enables cleanroom users to choose the areas where their product is believed to be most at risk. When the cleanroom is classified first, these locations will be sampled, and whenever the room is re-qualified the locations will be sampled again.
When combined together, these two methods provide improved confidence that the cleanroom is operating as expected and ideal for providing the right quality-controlled environment for life science applications. These methods are better than the method specified in the existing ISO 14644-1 document.

Improving Confidence in Quality

In addition to cleanroom monitoring and classification applications in the life sciences and pharmaceutical industries, there are certain particle counters that can be utilized in indoor air quality  and other less critical industrial applications.
Figure 1. Particle counters can be designed for different applications
Although a number of air particle counters available in the market are designed for use in all three application areas, some give incorrect results in low particle concentration environments such as life-critical cleanroom applications, while others are unable to handle high particle population environments found in the industrial applications. Therefore, particle counters developed for the less critical industrial applications may not meet the rigorous requirements specified in ISO 21501-4 and ISO 14644-3.

In an effort to enhance confidence in the quality of cleanroom environments, the amended ISO 14644-1 document will comprise the performance criteria of particle counter specified in ISO 14644-3 and give a normative reference to ISO 21501-4, Determination of particle size distribution — Single particle light interaction methods — Part 4: Light scattering airborne particle counter for clean spaces, to guide the reader through a consistent test method for the calibration of particle counters. The ISO 21501-4 document was initially published in 2007.

Additionally, manufacturers of particle counters and national standards agencies have publicized the normative reference to ISO 21501-4 in the amended document ever since the initial draft of the revised ISO 14644-1 document was published in December 2010. Therefore, the working group believed that, by the estimated publication date of the amended ISO 14644-1 in 2013, the industries using the ISO 14644-1 document would have sufficient notification of the need to conform to the ISO 21501-4 calibration method and to also upgrade any particle counters that are non-compliant.

Prior to the publication of ISO 21501-4 in 2007, no calibration standards were available for airborne particle counters which resulted in fluctuating levels of performance from particle counting systems. Since 2007, many particle counter manufacturers across the globe have modified the designs of their particle counters meant for critical life science ISO 14644 applications, so that these instruments can fulfill the more complex expectations of the latest calibration standard. Now, cleanroom users can have improved confidence that their cleanrooms are providing the required level of quality-controlled environment for their specific processes.

Content Imported from ISO 14644-3

The performance requirements of particle counter have been laid down in the ISO 14644-3 document since its first publication in 2005 and corresponds with the ISO 21501-4.

Figure 2. Specifications for the light-scattering discrete-particle counter from ISO 14644-3

In an effort to enhance clarity, the International Standards Organization Technical Committee ISO TC 209 determined that particle counter performance methods and criteria used to attain classification should be integrated into each ISO 14644 standard. Therefore, the performance criteria of particle counter specified in Table C.1 of ISO 14644-3 will appear in the amended ISO 14644-1 document.

Publication timeline

The initial publication of the Draft International Standard (DIS) DIS ISO 14644-1 in December 2010 triggered a heated debate. After assessing the questions and comments from the international community with regard to the DIS, the expert working group planned to publish an amended draft DIS document in 2013. In the interim, ISO Technical Committee TC209 recommends that users who want to leverage the improvements in the 2010 DIS ISO 14644-1 document can use it, as long as they know that the final published version will be modified.


The improved sampling method in the revised ISO 14644-1 document along with the enhanced guidance for particle counter calibration and performance will provide improved confidence to cleanroom users that their cleanroom is delivering the preferred level of quality-controlled environment for critical life science applications.

Posted by Tim Sandle

Pharmacopeial Forum Vol. 40 No.5: Sep– Oct 2014

A new edition of the Pharmacopeia Forum has been issued. Among the items of interest are:

Chapter 1041 -           Biologics (Revision proposal target, USP38-NF33 2nd Supplement)

USP propose revision of this General Chapter to update definitions, references and to explain compendial requirements and perspectives pertaining to this class of products and future monographs. Chapter <1041> is cross-referenced in the following general chapters and monographs.

General Notices, 5.50.10 Units of Potency (Biological). These citations will remain as written when the revised chapter text becomes official.

Chapter 1207 -           Sterile Product Packaging – Integrity Evaluation (Revision proposal target, USP38-NF33 2nd Supplement)

Chapter 1207 has been extensively revised and subdivided into four related chapters.

1207.1 - Package Integrity and Test Method Selection [NEW]
(Revision proposal target, USP38-NF33 2nd Supplement)

This proposed new general chapter describes a range of package integrity test methods that are used for ensuring sterile package integrity. Different types of package defects that cause leaks are described, and information about their detection is provided. Limit of detection is discussed in detail for the different leak test methods.

1207.2 - Package Integrity Leak Test Technologies [NEW]
(Revision proposal target, USP38-NF33 2nd Supplement)

This proposed new general information chapter provides information guiding the selection and proper use of leak test technologies. These leak test methods are divided into two major categories: deterministic and probabilistic. For each leak test technology, the chapter provides a description and discusses applications, test equipment, and test parameters.

1207.3 - Package Seal Quality Test Methods [NEW]
(Revision proposal target, USP38-NF33 2nd Supplement)

This proposed new general information chapter summarizes test methods useful for characterizing and monitoring package seal quality. These methods are not leak tests but provide additional data regarding package seal characteristics that may affect package integrity and leakage. The purpose of this chapter is to provide information to guide the selection and use of package seal quality test technologies.

1210 - Statistical Tools for Procedure Validation [NEW]
(Revision proposal target, USP38-NF33 2nd Supplement)

A new general information chapter is proposed as a companion chapter to Validation of Compendial Procedures, <1225> with the purpose of providing statistical methods that can be used in the validation of analytical procedures.

Posted by Tim Sandle

Wednesday, 12 November 2014

Bacterial endotoxins Ph. Eur. policy for substances for pharmaceutical use

The European Commission has made an important announcement about endotoxin limits in relation to substances for pharmaceutical use. For new substances, pharmacopeia monographs will no longer specify endotoxin limits. It will be left to the user to determine if a substance requires testing and what the appropriate limit should be.

The issued text reads:

Bacterial endotoxins Ph. Eur. policy for substances for pharmaceutical use (Approved by the Ph. Eur. Commission at its 149th Session, June 2014)

1.Reasons for requirements for testing for bacterial endotoxins

Bacterial endotoxins are contaminants from gram-negative bacteria and are the most common cause of pyrogenicity in pharmaceutical products. Any preparation administered parenterally should be sterile and comply with the test for bacterial endotoxins (BET) as described in the Ph. Eur.

Substances to be used in parenteral preparations must comply with the BET, whatever their origin, since:
  • Contamination by bacterial endotoxins can take place prior to or during the manufacturing process;
  • Bacterial endotoxins cannot easily be removed by the manufacturing process;
  • Bacterial endotoxins should be detected as early as possible in the manufacturing process.
  • It is to be noted that the ICH Guideline Q6B: Specifications: Test Procedures and Acceptance Criteria for Biotechnological/Biological Products provides the following recommendation under section 4.1 Drug Substance Specification: “Pharmacopoeial tests (e.g., endotoxin detection) should be performed on the drug substance, where appropriate.”

2. Requirements for bacterial endotoxins in the Ph. Eur.

The Ph. Eur. provides requirements for testing for bacterial endotoxins as follows.
The general monograph Substances for pharmaceutical use (2034) and individual monographs on substances for pharmaceutical use require compliance with the BET when substances are used in the manufacture of parenteral preparations. The monographs refer to general chapters 2.6.14. Bacterial endotoxins and 5.1.10. Guidelines for using the test for bacterial endotoxins.

According to the general monograph Parenteral preparations (0520), pharmaceutical preparations to be used parenterally have to comply with the test for bacterial endotoxins or, where justified and authorised, the test for pyrogens.

3. Problem statement

During the elaboration of a monograph, it is not always known at the level of the manufacturing of the substance whether the substance is to be used for the production of a parenteral preparation and therefore it is not known whether compliance with the BET is needed or not.

With regard to the limits to be applied for the test, individual monographs provide limits whereas general chapter 5.1.10 provides a way to calculate the endotoxin limit:

Values of K to be used for the calculation of the endotoxin depend on the route of administration and are given in the general chapter (Table 5.1.10.-1). There are other ways to establish limits, for example based on process capability, patient population or specific requirements of the competent authority. These are not clearly stated in the Ph. Eur. This might result in apparent contradictions between the different BET requirements.

4. New policy on the way to prescribe the BET in the Ph. Eur.

With consideration to the above, the Ph. Eur. Commission recommends the following approach to bacterial endotoxins.

Elaboration of new individual monographs

A test for bacterial endotoxins is not included in new monographs for substances for pharmaceutical use. The requirements of the general monograph Substances for pharmaceutical use (2034) apply.
  • A test is included only where a specific method has to be described, for example if a specific sample preparation has to be used or if a specific method has to be applied.
  • If a test is included in the monograph, no limit is given for the test.

Existing monographs

BET specifications are kept in individual monographs for substances for pharmaceutical use. Existing limits remain in individual monographs to maintain the use of well-established limits.

In order for the policy to be applied, the following changes are proposed to existing Ph. Eur. texts.
  • General chapter 5.1.10 is expanded with further considerations regarding the setting up of limits.
  • General monograph Substances for pharmaceutical use (2034) is slightly reworded in order to take the above policy into consideration.

5. Consequences of the new BET policy for Ph. Eur. users

It is up to the user of the Ph. Eur. to determine whether compliance to BET is needed or not for a given substance. Where a test is included in the monograph with no specific limit, it is up to the user to set the limit for the substance, based on the following considerations: use of the substance (route of administration, patient population); calculation according to the formula given in general chapter 5.1.10; process capability; or any other considerations raised by the competent authority.

Source: Ph. Eur.

Posted by Tim Sandle

Tuesday, 11 November 2014

Microbiology of serious human disease

Scientists at the University's Centre for Biomolecular Sciences have shed new light on how two proteins found on many human cells are targeted by the human pathogen Neisseria meningitidis which can cause life-threatening meningitis and septicaemia.

The proteins, laminin receptor (LAMR1) and galectin-3 (Gal-3) are found in and on the surface of many human cells. Previous research has shown they play diverse roles in a variety of infectious and non-infectious diseases. For example, the LAMR1 is a key receptor targeted by disease-causing pathogens and their toxins and is also a receptor for the spread of cancer around the body and for the development of Alzheimer's.

Using the latest bimolecular fluorescence and confocal imaging techniques, the researchers have shown that these two separate proteins can form pairs made up of two similar molecules (homodimers) or one of each molecule (heterodimers) which are targeted by Neisseria meningitidis. They have also identified critical components which cause the formation of these pairs of molecules.

These new mechanistic insights into the three-way relationship between proteins and bacterial pathogens could have significant implications in the fields of infection, vaccination and cancer biology.

For further details see:

F. Alqahtani, J. Mahdavi, L. M. Wheldon, M. Vassey, N. Pirinccioglu, P.-J. Royer, S. M. Qarani, S. Morroll, J. Stoof, N. D. Holliday, S. Y. Teo, N. J. Oldfield, K. G. Wooldridge, D. A. A. Ala'Aldeen. Deciphering the complex three-way interaction between the non-integrin laminin receptor, galectin-3 and Neisseria meningitidis. Open Biology, 2014; 4 (10): 140053 DOI: 10.1098/rsob.140053

Posted by Tim Sandle