Friday, 1 July 2016

ISO 9001 infographic



ISO 9001:2015 has arrived, it replaces ISO 9001:2008 and introduces a number of important changes. Check out our infographic to learn about ISO 9001’s history, the changes in the 2015 edition and our top five tips to transition.

SGS have produced a useful infographic about the changes to the standard. It can be viewed here.

Posted by Dr. Tim Sandle

Thursday, 30 June 2016

Prequalification of QC laboratories


The World health Organization (WHO) has released a new working document on how quality control laboratories qualify, in relation to GMP, for use by the United Nations.

The introduction reads:

“Participation in the prequalification procedure is voluntary and any pharmaceutical quality control laboratory (governmental or private) could participate. Certification such as ISO (in terms of ISO/IEC17025) is encouraged and will also be considered in the prequalification procedure. It is recommended that laboratories should work towards obtaining certification.

The quality assessment procedure established by WHO is based on the following principles:

– a general understanding of the quality assurance management and quality control testing
activities of the laboratory;

– evaluation of information submitted by the laboratory;

– assessment of compliance with WHO recommended quality standards for quality control
laboratories, i.e. GPCL  and the relevant parts of GMP; and

– monitoring of performance of prequalified laboratories.

The document can be viewed here.

Posted by Dr. Tim Sandle

Wednesday, 29 June 2016

Revision to cleanroom standard: ISO 14644 Parts 1 and 2



A new article has been published. This article reviews the key changes to International Organization for Standardization (ISO) standards document ISO 14644 Parts 1 and 2, in relation to cleanroom classification. The update requires those responsible for operating cleanrooms to consider some changes to current practice.

The reference is:

Sandle, T. (2016) Revision to cleanroom standard: ISO 14644 Parts 1 and 2, GMP Review, 15 (1): 4-7

For further details, please contact Tim Sandle



Posted by Dr. Tim Sandle

Tuesday, 28 June 2016

New ISO Standard for Validating Alternative Food Microbiology Methods

ISO 16140 for the validation of alternative (proprietary) microbiological methods has just been revised. The new multipart standard provides a specific protocol and guidelines for the validation of methods both proprietary (commercial) or not.

Two parts of ISO 16140 series now published:

ISO 16140-1:2016, Microbiology of the food chain - Method validation - Part 1: Vocabulary, describes the terminology used in microbial testing, while ISO 16140-2:2016, Microbiology of the food chain - Method validation - Part 2: Protocol for the validation of alternative (proprietary) methods against a reference method, is dedicated to the validation of proprietary microbiological methods. They are designed to help food and feed testing laboratories, test kit manufacturers, competent authorities, and food and feed business operators to implement microbiological methods. ISO 16140-2 includes two phases, the method comparison study and the interlaboratory study, with separate protocols for the validation of qualitative and quantitative microbiological methods.

For further details, see: ISO

Posted by Dr. Tim Sandle

India Releases New Biosimilars Guidance


India’s Central Drugs Standard Control Organization on Saturday released new guidance for biosimilar developers as new biosimilars come to market there before other regions, and as India's regulators look to develop more specific guidance on postmarketing studies.

The new document is a slight tweak of previous guidance issued in 2012, but includes several important changes that are now up for discussion through 30 April. India's biosimilars market currently includes eight biosimilars, including one for AbbVie's blockbuster Humira (adalimumab) and two biosimilars for Roche's breast cancer treatment Herceptin (trastuzumab), which are not approved in any other countries (though Korea's Food and Drug Administration has approved a different Herceptin biosimilar), according to the industry blog Biosimilarz (the Generics and Biosimilars Initiative lists more than 60 approved biosimilars in India).

For further details see: similars

Posted by Dr. Tim Sandle

Monday, 27 June 2016

Standards and controls for skin disinfection


The correct application of a suitable antiseptic is necessary to minimize the risk of surgical site infection. This class of infection accounts for about 15% of all health-care-associated infections in total and about 37% of the hospital-acquired infections of surgical patients.

The ideal antiseptic agent should be effective against a wide range of microorganisms; work within a fast onset of action; exert a long-term effect; and not be readily inactivated by organic material (e.g. blood). Moreover, it should have minimal toxic effects on the skin. Antiseptics can be classified as bactericidal (capable of killing most members of a population of microorganisms) or bacteriostatic (capable to inhibiting the growth of members of a population of microorganisms). In general, bactericidal products are preferred.

In relation to this, Tim Sandle has written a review article for The Clinical Services Journal. The reference is:

Sandle, T. (2016) Standards and controls for skin disinfection, The Clinical Services Journal, 15 (2): 25-28

For a copy, please contact Tim Sandle



 Posted by Dr. Tim Sandle

Sunday, 26 June 2016

Beneficial bacteria may protect breasts from cancer


Bacteria that have the potential to abet breast cancer are present in the breasts of cancer patients, while beneficial bacteria are more abundant in healthy breasts, where they may actually be protecting women from cancer, according to Gregor Reid, PhD, and his collaborators. These findings may lead ultimately to the use of probiotics to protect women against breast cancer. The research is published in the ahead of print June 24 in Applied and Environmental Microbiology, a journal of the American Society for Microbiology.
In the study, Reid's PhD student Camilla Urbaniak obtained breast tissues from 58 women who were undergoing lumpectomies or mastectomies for either benign (13 women) or cancerous (45 women) tumors, as well as from 23 healthy women who had undergone breast reductions or enhancements. They used DNA sequencing to identify bacteria from the tissues, and culturing to confirm that the organisms were alive. Reid is Professor of Surgery, and Microbiology & Immunology at Western University and Director, Canadian Centre for Human Microbiome and Probiotic Research at Lawson Health Research Institute in London, Ontario, Canada.
Women with breast cancer had elevated levels of Escherichia coli and Staphylococcus epidermidis, are known to induce double-stranded breaks in DNA in HeLa cells, which are cultured human cells. "Double-strand breaks are the most detrimental type of DNA damage and are caused by genotoxins, reactive oxygen species, and ionizing radiation," the investigators write. The repair mechanism for double-stranded breaks is highly error prone, and such errors can lead to cancer's development.
Conversely, Lactobacillus and Streptococcus, considered to be health-promoting bacteria, were more prevalent in healthy breasts than in cancerous ones. Both groups have anticarcinogenic properties. For example, natural killer cells are critical to controlling growth of tumors, and a low level of these immune cells is associated with increased incidence of breast cancer. Streptococcus thermophilus produces anti-oxidants that neutralize reactive oxygen species, which can cause DNA damage, and thus, cancer.
The motivation for the research was the knowledge that breast cancer decreases with breast feeding, said Reid. "Since human milk contains beneficial bacteria, we wondered if they might be playing a role in lowering the risk of cancer. Or, could other bacterial types influence cancer formation in the mammary gland in women who had never lactated? To even explore the question, we needed first to show that bacteria are indeed present in breast tissue." (They had showed that in earlier research.)
But lactation might not even be necessary to improve the bacterial flora of breasts. "Colleagues in Spain have shown that probiotic lactobacilli ingested by women can reach the mammary gland," said Reid. "Combined with our work, this raises the question, should women, especially those at risk for breast cancer, take probiotic lactobacilli to increase the proportion of beneficial bacteria in the breast? To date, researchers have not even considered such questions, and indeed some have balked at there being any link between bacteria and breast cancer or health."
Besides fighting cancer directly, it might be possible to increase the abundance of beneficial bacteria at the expense of harmful ones, through probiotics, said Reid. Antibiotics targeting bacteria that abet cancer might be another option for improving breast cancer management, said Reid.
In any case, something keeps bacteria in check on and in the breasts, as it does throughout the rest of the body, said Reid. "What if that something was other bacteria--in conjunction with the host immune system? We haven't answered this question, but it behooves experts in the field to now consider the potential."

Posted by Dr. Tim Sandle

Saturday, 25 June 2016

Comparability Protocols for Human Drugs and Biologics


The U.S. Food and Drug Administration has produced draft guidance for industry of interest. It is titled “Comparability Protocols for Human Drugs and Biologics: Chemistry, Manufacturing, and Controls Information.”

The introduction reads:

This guidance provides recommendations to holders of applications for human drugs and biologics on implementing a chemistry, manufacturing, and controls (CMC) postapproval change through the use of a comparability protocol (CP). It replaces the draft guidance that published in February 2003, titled Comparability Protocols: Chemistry, Manufacturing, and Controls Information.

A CP is a comprehensive, prospectively written plan for assessing the effect of a proposed CMC postapproval change(s) on the identity, strength, quality, purity, and potency of a drug product or a biological product (i.e., product), as these factors may relate to the safety or effectiveness of the product (i.e., product quality). Submission of a CP in an original application or prior approval supplement (PAS) allows the agency to review a description of one or more proposed CMC postapproval changes, supporting information including any analysis and risk assessment activities, a plan to implement the change(s), and, if appropriate, a proposed reduced reporting category for the change(s). Approval of the original application containing the CP or a subsequent PAS containing the CP can provide an applicant with an agreed-upon plan to implement the specified change(s), and in many cases, a justification to report the change(s) in a reduced reporting category, contingent upon the applicant’s analysis of the data from the implementation of the change…”

The document can be accessed here: FDA

Posted by Dr. Tim Sandle

Friday, 24 June 2016

Good Distribution Practice - Qualification of suppliers


The U.K. MHRA have produced a useful article about Good Distribution Practice. The article is titled “Good Distribution Practice - Qualification of suppliers, a helpful reminder of the 3 steps needed to assure supply chain integrity.”

The first step is to verify that supplies of medicinal products only come from persons who are themselves in possession of a wholesale distribution authorisation, or who are in possession of a manufacturing authorisation which covers the product in question.

The second step requires that wholesalers verify that any wholesale supplier complies with the principles and guidelines of good distribution practices.

The third step is periodic rechecking of the information obtained and due diligence.

The full post can be viewed here: GDP

Posted by Dr. Tim Sandle

Thursday, 23 June 2016

Pharmaciopeial Forum Vol. 42 No.3


Pharmaciopeial Forum Vol. 42 No.3

The Pharmacopeial Forum (draft texts relating to the USP) has been issued.


In relation to volume 42 (2), dated May - June 2016, the following is of interest to readers:

Chapter 621 Chromatography
(Revision proposal target, USP40-NF35 1st Supplement)

Additional changes are proposed for this chapter. Under System Suitability, Particle size (HPLC), it is proposed to delete the statement indicating that the high particle size in the “L” designation definition must be used when no particle size is mentioned in the monograph. Under System Suitability, Flow rate (GC), a proposed allowance for a linear velocity adjustment is being added.

Chapter 661.3 Plastic Components and Systems used in Pharmaceutical Manufacturing [proposed new chapter]
(Revision proposal target, USP40-NF35 1st Supplement)
This new chapter is proposed to address the qualification of plastic components used in the manufacture of both pharmaceutical and biopharmaceutical active pharmaceutical ingredients (APIs) and drug products (DPs). To support the use and understanding of this new general chapter, a section has been added to Evaluation of Plastic Packaging and Manufacturing Systems and Their Materials of Construction with respect to Their User Safety Impact 1661>This section, Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products, discusses material characterization and selection, and safety qualifications of plastic components and systems used to manufacture drug products.

This chapter is part of a suite of chapters, including Plastic Packaging Systems and Their Materials of Construction 661, Plastic Materials of Construction 661.1, Plastic Packaging Systems for Pharmaceutical Use 661.2, and 1661.

Chapter 1058  Analytical Instrument Qualification [proposed new chapter]
(Revision proposal target, USP40-NF35 1st Supplement)

In response to comments received the USP are proposing additional changes to this general information chapter.

Chapter 1661  Evaluation of Plastic Packaging Systems and their Materials of Construction with Respect to their User Safety Impact
(Revision proposal target, USP40-NF35 1st Supplement)

This chapter is being divided into two sections.
The first section, Plastic Packaging Systems and Their Materials of Construction, focuses on plastic materials of construction and packaging systems. The section describes all of the plastic materials that are included in Plastic Materials of Construction 661.1, the process of materials assessment, along with the applicability and application of 661.1. The chapter also goes on to discuss the importance of packaging system assessment and qualification and how Plastic Packaging Systems for Pharmaceutical Use 661.2 facilitates this assessment. With this revision, four new polymer descriptions are being added to the chapter [Polyamide 6; Polycarbonates; Poly(ethylene-vinyl acetate); and Polyvinyl chloride, non-plasticized], which corresponds to the addition of these materials to 661.1.

The second section, Plastic Components and Systems Used to Manufacture Pharmaceutical Drug Products, is meant to support the use and understanding of the new chapter Plastic Components and Systems Used in Pharmaceutical Manufacturing 661.3, appearing in the current PF.

Posted by Dr. Tim Sandle

Wednesday, 22 June 2016

Semi-synthetic bacterium created


Scientists have created a semi-synthetic, functioning bacterium in the lab that has fewer than 500 genes. The importance of "500" is that no bacterium in nature has less than 500 genes.

The organism "created" is Mycoplasma mycoides. The origins of the experiment date back to 2010, when a 1079-kb genome based organism was created. With the new experiment, a 531 kb (473 gene) version has been developed. "kb" refers to the genome size (the genome is the genetic material of an organism.) The essential unit is the "bp" or "base pair," the basic building block of DNA (for example, guanine-cytosine and adenine-thymine.)
In relation to the type organism in question, Mycoplasma are relatively less complex genus of bacteria that lack a cell wall around their cell membrane. The lack of a cell wall confers a resistance, to those strains that are pathogenic, to many types of antimicrobial compounds (including penicillin or other beta-lactam antibiotics.) With the specific species studied, M. mycoides is a parasite that lives in ruminants.
The 2010 study formed part of the part of the Minimal Genome Project. The project undertook the first complete cellular genome sequences of Mycoplasma organisms in 1995. This was of Haemophilus influenzae, a bacterium that causes many common childhood infections.
The 2010 experiment involved researchers synthesizing a modified version of M. mycoides (coded JCVI-syn1.0) and implanted it into a DNA-free bacterial shell of Mycoplasma capricolum. This other Mycoplasma species that had been emptied of its genome, and then "booted up" through the addition of JCVI-syn1.0.
The modified organism was capable of replication and therefore considered viable. To protect the "intellectual property," the researchers added a genetic watermark to the bacterium. The watermarks were coded messages in the form of DNA base pairs, of 1246, 1081, 1109 and 1222 base pairs respectively. The watermarks were not approved of by all in the scientific community, and were regarded by some geneticists as a publicity stunt.
The 2016 study, used genes from the JCVI-syn1.0 version to synthesize an even smaller genome. This has been coded JCVI-syn3.0. This is the organism with the 473 genes (531,560 base pairs.) With this, Syn 3.0 can operate with around 50 fewer genes that Syn1.0. The success indicates that organisms contain many genes needed for essential functions, but only a key number are required for actual life.
Discussing the research, lead scientist Dr. Daniel Gibson told the BBC: "Our long-term vision has been to design and build synthetic organisms on demand where you can add in specific functions and predict what the outcome is going to be."
Thus the aim of the research was two-fold. The first was to further understand the genetic basis of life. The second had a commercial aspect, and was designed to see if such research can provided the basis for manufacturing new drugs and chemicals. Microbial life is the basis of many pharmaceutical and chemical applications. This is the basis of "biotechnology", as the United Nations defines the science: "any technological application that uses biological systems, living organisms or derivatives thereof, to make or modify products or processes for specific use." The most likely future applications of the research rest with biofuel production or bioremediation (to clear up bio-waste, like oil spills.)
The research group behind the semi-synthetic bacterium project was backed by U.S. research entrepreneur Craig Venter. Venter is a biotechnologist, biochemist, geneticist by training. The founder of Celera Genomics, he was one of the first people to sequence the human genome.
An important point to make, and to avoid the 'wilder claims' made in some other media that have reported on this news, the modified bacterium is not a truly synthetic life form because its genome was put into an existing cell. One day the research institute aims to synthesize an organism consisting of only 256 genes, which is considered to be a minimal set of genes needed for viability. It should be noted that there is a difference between genes needed for "viability" an those required for "robust growth", simply creating a living organism doesn't mean the organism will grow particularly well. Moreover, it may only grow on a specially designed laboratory medium (with optimal nutrients) rather than in the natural environment.
To achieve this will require further painstaking studies: selectively removing each gene until the final number (and sequence) for minimal life is found. After this, it should be theoretically possible to design a genetic blueprint for a simple human-made bacterium. There is a way to go, however; of Syn 3.0's 473 necessary genes, the research indicates that 149 remain a scientific mystery in terms of their function. In relation to this, Jack Szostak, a biochemist at Harvard University who was not involved in the study, told Quantum Magazine, “To me, the most interesting thing is what it tells us about what we don’t know. So many genes of unknown function seem to be essential."
Such a move, where amino acids, fats and sugars could effectively be thrown together to create life, carries social and ethical considerations. Such a process could be used for good; however, it could also carry considerable risks, such as applications in biological warfare. To add fuel to the debate, Craig Venter told Forbes this was "the first designer organism in history."
The research is published in the journal Science, in a paper titled "Design and synthesis of a minimal bacterial genome."
This article is one of Digital Journal's Essential Science columns. Each week we explore a topical and important scientific issue. Last week we examined a theory that Jupiter had once bumped other proto-planets out of the way in its journey away from the Sun, billions of years ago. The previous week, a possible connection between viral and bacterial pathogens and the neurodegenerative disorder Alzheimer's disease was discussed.




Posted by Dr. Tim Sandle

Tuesday, 21 June 2016

Pharmaceutical Microbiology - Vote To Remain In Europe


The U.K. referendum taking place on June 23, on whether to remain or to leave the European Union, is being discussed on many levels, from the economic to the nationalistic. Another important area is science: will British science be better or worse in or out?

On this subject, Pharmaceutical Microbiology Resources website is supporting the vote for the U.K. to remain part of the European Union.

Looking at the scientific argument, a U.K. science base outside of the European Union would not access the funding it needs. For instance, one main route of funding is the Horizon 2020 initiative. Horizon 2020 is the financial instrument implementing the Innovation Union, a Europe 2020 flagship initiative aimed at securing Europe's global competitiveness.

Further arguments are centred on access to funding and uncertainty about future research collaboration. The EU produces over a third of the world’s scientific output. In addition, networking is crucial to being a world-leading science nation and U.K. scientists need to interact with European colleagues.

Another complication, should the U.K. pull out, is the issue of the recognition of professional qualifications.

This opinion is supported by a British government science policy committee, which recently concluded an inquiry by stating that European Union membership has been a crucial factor in shaping U.K. environmental policy on air and water pollution, and biodiversity.

To withdraw would lead to other adverse impacts – social, political, economic and cultural.

I believe that it benefits the U.K., the European Union, and global science for the U.K. to remain a strong committed member of the European Union.

Tim Sandle


USP #39 update


USP39-NF34 became official on 01 May 2016.

Items of interest include:

Apparatus for Tests and Assays

Chapter 21      Thermometers [This has been deleted]

Biological Tests and Assays

Chapter 162 Diphtheria Antitoxin Potency Testing for Human Immune Globulins [This is a new chapter]

An in vitro method is provided that is suitable for determining the potency of diphtheria antitoxin (antibodies against the diphtheria toxin) in preparations of plasma-derived human immune globulins. Diphtheria toxin is produced by Corynebacterium diphtheriae and has the ability to produce a cytopathogenic effect on susceptible epithelial cell lines. The test is based on the ability of diphtheria antitoxin to neutralize the diphtheria toxin, decreasing its cytotoxic effect. Specifically, the test determines the potency of the diphtheria antitoxin based on its ability to inhibit the cytotoxic effect of diphtheria toxin on cultured Vero cells (African green monkey kidney epithelial cells) relative to a reference standard. The mitochondrial dehydrogenases of live Vero cells can reduce the dye 3-4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) to a blue/black product that is then measured by absorbance at 540 nm. If no or little diphtheria antitoxin is present, then diphtheria toxin induces cell death and the inability of cells to reduce MTT, resulting in the presence of white or colorless wells. Acceptance criteria are defined by the appropriate regulatory agencies.

With the 1st supplement (effective 1st August 2016):

Chapter 87      Biological Reactivity Tests, In Vitro

Test Control and USP Reference Standards

Chemical Tests and Assays

Chapter 191    Identification Tests-General

Introduction, Chemical Identification Tests, and Instrumental Identification Tests

Chapter 507    Protein Determination Procedures [New chapter]

Physical Tests and Determinations

Chapter 791    pH

Introduction, Instrument Requirements, Buffer Solutions for Calibration of the pH Measurement System, Calibration, and Operation.

Chapter 1035 Biological Indicators for Sterilisation [Chapter deleted]

Chapters added:

1207 Package Integrity Evaluation- Sterile Products
1207.1 Package Integrity Testing in the Product Life Cycle – Test Method Selection and Validation
1207.2 Package Integrity Leak Test Technologies
1207.3 Package Seal Quality Test Technologies
1228    Depyrogenation
1228.1 Dry Heat Depyrogenation
1229.5 Biological Indicators for Sterilisation
1229.9 Physicochemical Integrators and Indicators for Sterilisation
1229.12 New Sterilisation Methods

Chapters deleted:

1209 Sterilisation- Chemical and Physicochemical Indicators and Integrators


With the 2nd supplement (effective on 1st December 2016):

General Information

1029 Good Documentation Guidelines{ New chapter]
1228.3 Depyrogenation by Filtration [New chapter]
1228.5 Endotoxin Indicators for Depyrogenation [New chapter]
1229.13 Sterilisation-in-Place [New chapter]
1231    Water for Pharmaceutical Purposes [revise chapter]



Posted by Dr. Tim Sandle

Monday, 20 June 2016

Cleaning efficiency for glassware in the pharmaceutical microbiology laboratory


The cleaning of glassware is an important preliminary step prior to sterilisation in the microbiology laboratory. If insufficient cleaning takes place, residues of culture media and chemicals can remain and these could potentially have an impact upon microbial growth during various microbiological qualitative and quantitative tests. This paper outlines a study where four different manual cleaning regimes were used to evaluate glassware cleaning. It was found that a 5% solution of neutral detergent, followed by two rinses was the most efficient method. The experiment is put forward as a case study for other laboratories to replicate as necessary.

In relation to this, Tim Sandle and Ravikrishna Satyada have written a new research paper.

The reference is:

Sandle, T. and Satyada, R. (2016) Determination of the cleaning efficiency for glassware in the pharmaceutical microbiology laboratory, European Journal of Parenteral & Pharmaceutical Sciences; 21(1): 16-22

For further details, please contact Tim Sandle



Posted by Dr. Tim Sandle

Sunday, 19 June 2016

Using Bacteria To Power A Robot


Bacteria can be used to power a micro-sized robot by propelling it in a certain direction. This is remarkable enough, but now engineers and microbiologists have managed to fully control the direction and avoid obstacles on the way.
The devices in question are called “bio-robots” and they are essentially a computer chips coated with motile bacteria (motile because they possess flagella, which act as propellers – the bacterium used is called Serratia marcescens). The idea of the bio-chips is to deliver medicine to cells in the human body.
Researchers developed a novel method, using electric fields to help micro bacteria-powered robots detect obstacles in their environment and navigate around them to get to their goal (Drexel.edu)
Researchers at Drexel University have managed to control the movement of the bio-chips to the level of precision needed to target cells with medicine. This is through using electric fields to direct the bacteria within a fluid. This is made possible because the bacteria adhered to the chip possess a negative charge; thereby varying an external charge source, the movement the bacteria take (direction and distance) can be controlled.
Essentially the process uses two perpendicular electric fields that turn the fluid into an electrified grid. By varying the charge, the course and speed alter; to do this requires a precise computer program. The technique has yet to be tried out in a person, but the results are promising enough to pursue this longer-term experimental aim.
As this tiny robots respond by electric fields that bend around static obstacles, bio microrobots can detect the obstructions and adjust their course (Drexel.edu)
The research has been published in IEEE Transactions on Robotics. The research paper is headed “Electric Field Control of Bacteria-Powered Microrobots Using a Static Obstacle Avoidance Algorithm.”

Posted by Dr. Tim Sandle