Monday, 22 January 2018

Application of ISO 14644 Parts 1 and 2 for cleanroom contamination control


Cleanrooms are highly controlled environments, defined the air quality, and where certain physical and microbiological requirements need to be met.  Air quality is achieved through a combination of airborne particulate control, such as through High Efficiency Particulate Air (HEPA) filters; high fresh air rates (air movement and air changes); clean-up (or ‘recovery’) times; pressure differentials, which concerns air direction; temperature and humidity control (where necessary); cleaning and disinfection; and staff behaviors and gowning. The requirements for air quality, and the associated physical aspects designed to achieve this, are contained within the international standard ISO 14644.

To examine the requirements of Parts 1 and 2 of the standard in relation to contamination control in cleanrooms, Tim Sandle has written a chapter for Volume 8 of the ongoing Environmental Monitoring: A Comprehensive Handbook series.

Different types of cleanrooms require different levels of control to achieve the desired level of cleanliness. The required standard of cleanliness of a room will relate to the type of task performed in it and it follows that the more susceptible the product is to contamination, the better (“cleaner”) the standard that is accepted. The chapter explores this principle from the perspective of microbiological risk,

The reference is:

Sandle, T. (2017) Application of ISO 14644 Parts 1 and 2 for cleanroom contamination control. In Moldenhauer, J. (Ed.) Environmental Monitoring: A Comprehensive Handbook, Volume 8, DHI Publoshing / PDA, River Grove, IL, USA, pp3-22

Posted by Dr. Tim Sandle

Sunday, 21 January 2018

Webinar - Investigating Sterility Test Failures

New webinar - January 25, 2018

Date: Thursday, 25 January 2018 | Time: 10:00 AM PST, 01:00 PM EST | Duration: 60 Minutes

Sterility testing is widely used in both the medical device and pharmaceutical industries. The pharmacopeia test is the official procedure for testing the sterility of pharmaceutical products. Despite its importance and its widespread use, many people are not aware of the limitations of the sterility test and are unsure how to proceed when a failure investigation occurs.


Instructor: Tim Sandle
Product ID: 503878

Questions to help with this process, like -- "Can the test be invalidated? Is the product rejected? What needs to be investigated? How is root cause established? What need to be done before production can resume?"-- will be answered in this webinar.

Objectives of the Presentation

  • What the sterility test can and cannot demonstrate
  • The causes of sterility test failures
  • The actions required on being notified of a failure, including deviation management and quarantine
  • Best practices for laboratory test investigations
  • Best practices for processing investigations
  • Best practices for aseptic processing investigations
  • Developing a remediation plan including the necessity for media simulation trialsWhy Should you Attend
  • To gain an insight into the best practices for sterility test failure investigations, from a speaker who has presented sterility test failure investigation reports to both FDA and European Medicines Agency inspectors.

Areas Covered

  • History of the sterility test
  • Statistical limitations of the sterility test
  • Actions required by management on being notified of a sterility test failure
  • The importance of genotypic microbial investigation
  • Points to consider for investigating testing, such as cleanroom or isolator operational parameters
  • Reviewing major contamination incidences in process areas that could lead to a sterility failure, from raw materials to wet equipment
  • Detailed forensics for aseptic process investigations, such as reviewing people, processes and equipment
  • How to do put an investigation report together
  • How to test out CAPA through media fills
  • What to do if the investigation is inconclusive
For details, see Online Compliance Panel.

SCREEN United Kingdom Cargo Theft Report Q3 2017


BSI and the National Vehicle Crime Intelligence Service (NaVCIS) have come together to develop a robust report to provide increased visibility into cargo theft threats across the United Kingdom. BSI recorded a total of 296 cargo theft incidents in the United Kingdom during the third quarter of 2017, with nearly 63% of them involving the slash-and-grab tactic and 18% involving theft from hard-sided trucks. BSI recently held a webinar to review our findings, including:

Q3 United Kingdom cargo theft analysis
County breakdown of the top cargo theft threats in the United Kingdom
Top targeted commodities, methods and locations of thefts, and areas of concern

To access the webinar recording, please click here.

To download the newly released report, click here.

Posted by Dr. Tim Sandle

Saturday, 20 January 2018

Is Alzheimer’s caused by bacteriophages?


Scientists have reported on a breakthrough that may change conventional understanding of causes for many diseases like Alzheimer’s. This relates to viruses called bacteriophages. To find out more we spoke with Dr. George Tetz.


Dr. George Tetz has led a research team that has recently presented important data that could change the conventional medical understanding of causes for many diseases, like Alzheimer’s disease, together with other neurodegenerative diseases.

This is that neurodegenerative diseases can be caused by bacteriophages. These are viruses that infect and replicate within bacteria. In the context of the new research, this is with the gut microbiota of humans and other mammals.

Dr. Tetz is involved with the Human Microbiology Institute, which is based in New York. To find out more, Digital Journal spoke with the researcher about the last findings and their implications.

See: http://www.digitaljournal.com/tech-and-science/science/interview-is-alzheimer-s-caused-by-bacteriophages/article/507260#ixzz4yvIfOfdVe

Friday, 19 January 2018

Are Phages Our Best Bet Against Antibiotic-Resistant Bacteria?


Bacteriophages, or simply phages, are viruses that infect and replicate within bacteria, and they hold considerable potential for combatting antibiotic-resistance and other threats to human health. Timed with the hundredth anniversary of their discovery, a new review published in the British Journal of Pharmacology examines the challenges and opportunities of developing phages as health-promoting, commercially-viable biopharmaceuticals.

In the review, Amanda Forde, PhD, and Colin Hill, PhD, of the APC Microbiome Institute at University College Cork, in Ireland, note that phages have complex relationships with bacteria in the gut that could affect health and disease. “Through an intricate 'predator-prey' strategy, phages have the ability to alter the microbial balance within an ecosystem, and given that they are the most abundant biological entities on earth, it would be odd to ignore or underestimate their power and potential,” said Dr. Forde. She explained that phages outnumber their bacterial prey by a factor of 10 to 1, and that they have been proposed as the agents of change in recipients of faecal microbiota transplantations used to treat resistant or recurring bowel disease.

“We tend to think of phages as nature's 'nano-machines', self-assembling complex biological survival machines capable of replicating faster than any other biological agent,” said Dr. Hill. “They are highly diverse, highly dynamic, and highly specific to their targets, and as antibiotic-resistant 'superbugs' continue to emerge around the world, they may be among our best allies in the future.”

Despite having been discovered a century ago, their use in clinical therapy continues to encounter several challenges. “One of the challenges lies in the fact that more than 90% of phage populations are as yet unidentified, and therefore considered to be the 'dark matter' of the biological world,” said Dr. Hill. “Coupled with manufacturing challenges, regulatory hurdles and the need for clinical validation, the path to pharma may seem long, but researchers are heading in the right direction.”

Phages were used for more than 75 years as therapy in Eastern Europe, but they fell out of favour in the western world when antibiotics were discovered. They are now becoming attractive again because of the rise in antibiotic resistance. A unique selling point is their host specificity, meaning little or no collateral damage to neighbouring ('good') bacteria, and they do not drive the development of resistance in non-target bacterial species.

“Whilst regulated phage therapy may take some time, it has been highly successful in recent 'compassionate' cases where patients’ lives were on the line,” said Dr. Forde. “But for regulated interventions, we need to play the waiting game as more genomic, physiological, pharmacological, and clinical data are gathered. And wait we will.”
Posted by Dr. Tim Sandle

Thursday, 18 January 2018

Single sand grain harbors up to 100,000 microorganisms


Just imagine, you are sitting on a sunny beach, contentedly letting the warm sand trickle through your fingers. Millions of sand grains. What you probably can't imagine: at the same time, billions upon billions of bacteria are also trickling through your fingers. Between 10,000 and 100,000 microorganisms live on each single grain of sand, as revealed in a new study.

It has long been known that sand is a densely populated and active habitat. Now David Probandt and his colleagues have described the microbial community on a single grain of sand using modern molecular methods. To do this, they used samples taken from the southern North Sea, near the island of Helgoland, off the German coast.

The bacteria do not colonize the sand grains uniformly. While exposed areas are practically uncolonized, the bacteria bustle in cracks and depressions. "They are well protected there," explains Probandt. < "When water flows around the grains of sand and they are swirled around, rubbing against each other, the bacteria are safe within these depressions." These sites may also act as hiding grounds from predators, who comb the surface of the sand grains in search of food.

However, the diversity of the bacteria, and not just their numbers, is impressive. "We found thousands of different species of bacteria on each individual grain of sand," says Probandt.

Some bacteria species and groups can be found on all investigated sand grains, others only here and there. "More than half of the inhabitants on all grains are the same. We assume that this core community on all sand grains displays a similar function," explains Probandt. "In principle, each grain has the same fundamental population and infrastructure." We can therefore really discover a great deal about the bacterial diversity of sand in general from investigating a single grain of sand.

Sand-dwelling bacteria play an important role in the marine ecosystem and global material cycles. Because these bacteria process, for example, carbon and nitrogen compounds from seawater and fluvial inflows, the sand acts as an enormous purifying filter. Much of what is flushed into the seabed by seawater doesn't come back out.

See:

David Probandt, Thilo Eickhorst, Andreas Ellrott, Rudolf Amann, Katrin Knittel. Microbial life on a sand grain: from bulk sediment to single grainsThe ISME Journal, 2017; DOI: 10.1038/ismej.2017.197

Posted by Dr. Tim Sandle

Wednesday, 17 January 2018

How to comment on Draft EU GMP Annex 1


News from the European Medicines Agency:

Targeted stakeholders consultation on the revision of annex 1, on manufacturing of sterile medicinal products, of the Eudralex volume 4

Period of consultation

From 20 December 2017 to 20 March 2018.

Objective of the consultation

Annex 1 was first published in 1971, since then it has undergone a number of targeted updates but, until now it has not undergone a full review. This revision is intended to add clarity, introduce the principles of Quality Risk Management to allow for the inclusion of new technologies and innovative processes and to change the structure to a more logical flow. Key changes are:
  • Introduction of new sections: scope, utilities, Environmental and process monitoring sections and glossary 
  • Introduction of QRM Principles 
  • Restructured to give more logical flow 
  • Added detail to a number of the previous sections to provide further clarity. 
Acknowledgment

In order to maintain the global alignment of standards, achieving at the same time assurance for the highest quality, the proposed revised version was prepared in cooperation with WHO and PIC/S. The document will be subject to parallel public consultation by WHO and PIC/S.

How to submit your contribution

Please provide feedback using the template enclosed sending it to SANTE-REVISION-ANNEX-1@ec.europa.eu.

They can also be sent by post to Directorate-General for Health and Food Safety, Unit SANTE B/4, BE-1049 Brussels. The subject line of the letter or email should contain the reference "Targeted Public Consultation – Revision of annex 1 of EU GMP Guide".

When submitting your response, please include your name and e-mail address and specify if you are responding as an individual or as a representative of an organisation. If you represent an organisation, please indicate its name and category (company/business; public authority (local, regional, national, international); NGO; patient organisation; other).

If you represent a company, please state whether it falls within the EU definition of a small and medium-sized enterprise (i.e. less than €50 million annual turnover and fewer than 250 employees).

If your organisation is registered in the Transparency Register, please indicate your Register ID number at the beginning of your contribution.

The consultation document

The consultation document can be downloaded here.

The template for comments can be downloaded here.

Contact details

Responsible service: Directorate-General for Health and Food Safety - Unit B4 - Medical Products: quality, safety, innovation.

E-mail: SANTE-REVISION-ANNEX-1@ec.europa.eu

Any queries about the public consultation should be sent to this mailbox.

Tuesday, 16 January 2018

Procedural guidance to help pharma companies prepare for Brexit

The European Medicines Agency (EMA) has published procedural guidance to help pharmaceutical companies prepare for the United Kingdom’s (UK) withdrawal from the European Union (EU).

The guidance document outlines the practical and simplified requirements that companies should follow when they apply for changes to their marketing authorisation to allow for the continued marketing of their medicine in the European Economic Area after the UK withdraws from the EU. The guidance has been prepared on the basis that the UK will become a third country as of 30 March 2019. It should be read in conjunction with the Questions and answers related to the United Kingdom's withdrawal from the European Union with regard to the medicinal products for human and veterinary use within the framework of the centralised procedure published in May 2017.

Marketing authorisation holders, applicants and sponsors of centrally authorised medicines for human or veterinary use should consider how Brexit will impact their medicines and which changes need to be addressed before the UK leaves the EU. They also need to ensure that the necessary changes are made by that date.

EMA is preparing a series of further Brexit-related guidance which will be published on its website in due course. Companies are advised to regularly check EMA’s dedicated webpage on the consequences of Brexit.

See also: Questions and Answers related to the United Kingdom's withdrawal from the European Union with regard to the medicinal products for human and veterinary use within the framework of the Centralised Procedure
Posted by Dr. Tim Sandle

Monday, 15 January 2018

Sterilization of Microbiological Culture Media


Culture media, even in the emerging era of rapid microbiological methods (and notwithstanding that many rapid methods are culture-based), continues to remain a fundamental tool in the pharmaceutical and healthcare microbiology laboratory.

Tim Sandle has written a new peer-reviewed paper. Here is an exact:

Culture media is an important part of pharmaceutical microbiology: to enumerate and identify microorganisms . Control of culture media, in terms of appropriate records through to plate reading, forms an important part of data integrity in the microbiology laboratory (as assessed by Saha (2016) and Sandle (2016).

Media is devised on the basis of microorganisms requiring nutrients in order to grow. These nutrients are formulated and supplied by either solid or liquid culture media. The standard solid medium is a type of nutrient agar, a gelatinous substance derived from seaweed. The standard liquid medium is a type of nutrient broth, composed of water, meat extract peptone, and sodium chloride. While many aspects of the manufacture and use of culture media are well-described, the aim of this article is to pinpoint one of those aspects that is not always adequately and this which can lead to errors: sterilization.

The reference is:

Sandle, T. (2017) Sterilization of Microbiological Culture Media, Journal of GxP Compliance, 21 (5): 13-22, at: http://www.ivtnetwork.com/article/microbiological-aspects-cleaning-validation

For further details contact Tim Sandle: pseudomonas@btinternet.com

Sunday, 14 January 2018

Turning pathogens against each other to prevent drug resistance


Limiting a much-needed resource could pit pathogens against one another and prevent the emergence of drug resistance. New research demonstrates that harnessing competition among pathogens inside a patient could extend the life of existing drugs where resistance is already present and prevent resistance to new drugs from emerging.

Drug resistance originates when a pathogen -- such as a parasite, virus, or bacterium -- develops a genetic mutation that allows it to avoid being killed by the drug. Even if only one individual pathogen has this mutation, as is frequently the case when resistance first arises, that one individual can replicate into a population of billions once it survives drug treatment. But resistance often comes with a cost, and drug-resistant pathogens often do not acquire certain resources as efficiently as other pathogens, or they may require more of the resource.

The researchers manipulated a nutrient in the drinking water of mice that is used by malaria parasites during an infection -- just as a gardener might manipulate nutrients through fertilizers to favor certain plants. This dietary intervention was used alongside traditional drugs as a sort of combination therapy.

The researchers then confirmed that their results were due to competition among parasites and not some other effect of limiting the nutrient. When drug-treated mice were infected only with resistant strains and the nutrient was limited, the resistant parasites survived. But when drug-treated mice were infected with both sensitive and resistant parasites, limiting the nutrient stopped resistant parasites from growing at all -- even when resistant parasites were initially present at far greater numbers than when they typically first appear in a host.

See: Penn State University for further details.

Posted by Dr. Tim Sandle

Saturday, 13 January 2018

Reclassification of Propionibacterium acnes


The bacterium Propionibacterium acnes has been reclassified as Cutibacterium acnes, based on discrepancies between the phylogenetic signals of 16S rRNA gene sequence analysis and high-resolution core-genome analysis.

The former P. acnes is a bacterium associated with the outer layers of the human skin and it has an association with sterility test failures. 

The reference for the change is:

Scholz, C.F.P. and Kilian, M. (2016) The natural history of cutaneous propionibacteria, and reclassification of selected species within the genus Propionibacterium to the proposed novel genera Acidipropionibacterium gen. nov., Cutibacterium gen. nov. and Pseudopropionibacterium gen. nov., International Journal of Systematic and Evolutionary Microbiology, 66, 4422–4432

Here is the abstract to the paper:

The genus Propionibacterium in the family Propionibacteriaceae consists of species of various habitats, including mature cheese, cattle rumen and human skin. Traditionally, these species have been grouped as either classical or cutaneous propionibacteria based on characteristic phenotypes and source of isolation. To re-evaluate the taxonomy of the family and to elucidate the interspecies relatedness we compared 162 public whole-genome sequences of strains representing species of the family Propionibacteriaceae. We found substantial discrepancies between the phylogenetic signals of 16S rRNA gene sequence analysis and our high-resolution core-genome analysis. To accommodate these discrepancies, and to address the long-standing issue of the taxonomically problematic Propionibacterium propionicum, we propose three novel genera, Acidipropionibacterium gen. nov., Cutibacterium gen. nov. and Pseudopropionibacterium gen. nov., and an amended description of the genus Propionibacterium. Furthermore, our genome-based analyses support the amounting evidence that the subdivision of Propionibacterium freudenreichii into subspecies is not warranted. Our proposals are supported by phylogenetic analyses, DNA G+C content, peptidoglycan composition and patterns of the gene losses and acquisitions in the cutaneous propionibacteria during their adaptation to the human host.

The paper can be found online here.

Posted by Dr. Tim Sandle

Friday, 12 January 2018

A New Technology Can be Used Instead of Antibiotics to Kill Superbugs

Dr. Timothy Lu, an associate professor in biological engineering at the Massachusetts Institute of Technology, found a new potential way to kill superbugs with a DNA editor called CRISPR-Cas9. The Wall Street Journalreported that Dr. Lu said: “is is basically a molecular scissor” that can snip bacterial genes that make bacteria drug-resistant, killing the bug in the process. The technology combines bacteriophages and CRISPR-Cas9 to target drug-resistant genes.

Dr. Lu is studying ways to eliminate superbugs with CRISPR-Cas9. He is contemplating combining the CRISPR-Cas9 technology with bacteriophages, and engineering the bacteriophages to attack only bacteria with drug-resistant genes. They were successful in including the CRISPR-Cas9 into a bacteriophage that was designed to attack a drug-resistant E. coli (Nature Biotechnology, 2014 Sequence-specific antimicrobials using efficiently delivered RNA-guided nucleases, R. J. Citorik, M. Mmee, and T. K. Lu). The new technology has the advantage of being a more targeted approach.



Numerous hurdles need to be overcome before this technology can be used against superbugs, including the demonstration that in humans, bacteriophages are safe and effective to use. Another concern is that the CRISPR can deviate from the target, thereby slicing the wrong genes. However, there is a race among scientists to find new applications for this novel technology.

One major concern is that CRISPER can veer off target, slicing away the wrong genes with potentially harmful effects, scientists say. There are also fears of unknown effects due to the use of CRISPER to modify bacteria. Regardless of the promise of this technology, any potential therapy is years away. Nevertheless, many other scientists are trying to harness this novel technology for a variety of applications.

Source: Bio Expert

Thursday, 11 January 2018

Overuse of antibiotics in farming is a major new threat to human health


Antibiotics that has spilled from farms into the natural environment may be a bigger factor in spreading resistance to life-saving drugs than previously thought, U.N. report says.

The overuse of antibiotics in farming has been highlighted as one of the biggest emerging threats to human health, spreading resistance to vital drugs and endangering millions of lives.

Antibiotics used on farms can spill over into the surrounding environment, for instance through water run-off and slurry, according to a report from the UN’s environment body, with the potential to create resistance to the drugs across a wide area.

This environmental diffusion of powerful medicines, to which bacteria are increasingly gaining resistance, is rendering even the drugs of last resort ineffective in human treatment, and may be a bigger factor in spreading resistance than had been thought. Previous concerns focused on resistance to the drugs among livestock and farm workers, but the UN report says the problem goes much further and is much more dangerous.

From The Guardian - read more here.

Wednesday, 10 January 2018

A focus on regulatory trends: MHRA annual deficiency review


Tim Sandle and Clare Leavy have reviewed the latest report from the MHRA looking at the major regulatory findings for 2016. In the review the key trends are broken down into ‘hot topics’ and the key findings discussed.

For the past three years, the U.K. Medicines and Healthcare products Regulatory Agency (MHRA) has produced information summarizing key inspectorate trends. With each successive year the level of detail provide with the headline trends has been made more comprehensive. The most recent review (2016) is notable for the appearance of ‘sterility assurance’ in the top ten key categories of inspectorate trends. Not only does this subject appear on the list for the first time, it occupies the number two spot.

This includes: management, water systems, aseptic processing, microbiology laboratories, aseptic connections, personnel gowning, data integrity, staff training and cleaning and disinfection.

The reference is:

Sandle, T. and Leavy, C. (2017) A focus on regulatory trends: MHRA annual deficiency review, Pharmig News, Issue 69, pp2-5

For further information, contact Tim Sandle

Posted by Dr. Tim Sandle

Tuesday, 9 January 2018

Pharmig conference report

The new to invest in new technologies and a call for a new paradigm for approaching risk assessment were the keynote messages from the 2017 Pharmig conference, which focused on making medicines safe for patients.

Despite innovations in rapid microbiological methods the pharmaceutical sector has been slow to adopt the latest technologies; moreover, the approach to assessing the risks to products is too often rooted in poor science and an over-reliance upon scoring every tiny detail with an arbitrary number. These were the messages delivered by a pharmaceutical regulator and one of the world’s foremost pharmaceutical microbiologists.

The Pharmaceutical Microbiology Interest Group (Pharmig) hosts an annual conference each year in the U.K. This year’s event took place at Heythrop Park, part Grade II listed Baroque building designed for the Duke of Shrewsbury, and part modern conference center.

The conference opened with addresses from two former chairs of Pharmig: Sharon Johnson and David Begg. Begg called on the industry not to forget what really matters - protecting patients; and Johnson queried why progress with the adoption of rapid methods was so slow.
David Begg  a former medicines inspector  addresses the 2017 Pharmig conference.
David Begg, a former medicines inspector, addresses the 2017 Pharmig conference.
Need for a less conservative pharmaceutical industry
The call for the pharmaceutical industry to be less conservative with the adoption of rapid microbiological methods came from healthcare regulator Andrew Hopkins (the pertinent points from his presentation are discussed in the article “Rapid methods needed to help safety of medicines”). Hopkins stressed that better dialogue was required between regulators and pharmaceutical manufacturers, and he outlined a forum that can be used for this purpose.
One of the exhibition stands at the Pharmig conference  with a display of the special clothing requi...
One of the exhibition stands at the Pharmig conference, with a display of the special clothing required to access production areas.
The need for a renewed focus on risk assessment came from Dr. Edward Tidswell (Merck-U.S.), who is also an expert in how microorganisms adhere to surfaces and co-editor of the book “Aseptic and Sterile Processing: Control, Compliance and Future Trends”. Dr. Tidswell, in conjunction with Kevin O’Donnell, who represents the Irish regulator agency the HPRA, said that too many risk assessments are based on a lack of data and use a poorly conceived scoring system. Called out for greatest criticism was ‘Failure Modes and Effects Analysis’ (FMEA), a risk tool commonly used in the engineering sector.
Dr. Edward Tidswell address the 2017 Pharmig conference.
Dr. Edward Tidswell address the 2017 Pharmig conference.
New paradigm for risk management
Instead, Dr. Tidswell said, quantitative risk management was needed - real-time data and lots of it. Only through big data analytics, the pharmaceutical microbiologist stated, can risks of microbial contamination transfer to a pharmaceutical product be truly understood and quantified. For this to work, and in a link back to the presentation made by Hopkins, a greater adoption of rapid methods is needed. Hence both new approaches to risk assessment and rapid methods are needed for the digital transformation of pharmaceutical microbiology.
Examples of rapid microbiological methods on show at the Pharmig conference  including real-time bio...
Examples of rapid microbiological methods on show at the Pharmig conference, including real-time biologica air-samplers.
Another presentation of note was delivered by Professor Willy Verstraete of the University of
Ghent, Belgium. This presentation looked at ecological microbiology and how understanding microbial communities better is the basis for better environmental control, especially in relation to agriculture. Here biotechnology, such as the use of nitrogen-utilizing bacteria in bioreactors, can be used for such innovations as microbial protein to be used as a meat substitute. For more on Professor Verstraete’s treatise see the article “Will microbial protein replace meat on the table?"
New microbial contamination concerns
Contamination of pharmaceutical products with water-borne organisms was a theme addressed in two presentations. The first was a case study outlined by Geert Verdonk, from the German pharmaceutical giant Merck. The second was a regulatory perspective given by Dr. John Metcalfe, from the U.S. Food and Drug Administration (FDA).
David Keen  chair of Pharmig  addresses the 2017 conference.
David Keen, chair of Pharmig, addresses the 2017 conference.
In these presentations that growing regulatory focus on the organisms that form the Burkholderia Cepacia Complex was detailed, especially in relation to non-sterile pharmaceutical products. Burkholderia Cepacia Complex is a group of some twenty organisms; bacteria that are naturally resistant to many common antibiotics and thereby posing a public health hazard. If pharmaceutical products are contaminated with such organisms, then based on the patient population and the total bioburden, this would pose a risk of serious illness.

According to Dr. Metcalfe it is beholden upon pharmaceutical manufacturers to stablish procedures to prevent these objectionable microorganism contaminating of drug products. This includes having adequate procedures to assure adequate quality of incoming materials; ensuing processes are of sanitary design with appropriate maintenance and cleaning of equipment. In addition there should be production and storage time limitations, supported by the monitoring of environmental conditions.
Delegates meeting with exhibitors at the Pharmig 2017 conference.
Delegates meeting with exhibitors at the Pharmig 2017 conference.
Sanitary design was discussed by another presenter, Neil Lewis who is the Global Household Care Microbiologist at Proctor and Gamble. This looked at how alternative methodologies can be used to assess the cleanliness of equipment, arguing that legacy approaches to do not adequately address microbial risks.
New technologies on the horizon
The new technology theme was continued by Dr. Mark Sutton, who works for Public Health England. Dr. Dutton has developed an alternative means for assessing biodecontamination of clean areas. Instead of the sometimes imprecise method of adding bacterial spores onto strips of paper or stainless steel to assess microbial kill, Dr. Sutton is proposing an enzymatic test using thermostable Adenylate Kinase. This enzyme is found in all cells and it plays a role in cellular energy homeostasis.

Other presentations took different directions. Les Meader, who runs two companies - Omnia CS and Foresight Innovations Limited, discussed why human error occurs and how understanding this can be applied to pharmaceutical and healthcare manufacturing. Understanding human psychology, Meader argued, is necessary if processes are to be designed in an optimal way as so to reduce people related mistakes.

The theme of training was central to new a digital training module developed by Pharmig for those tasked with cleaning and disinfection. The online platform uses digital technology and e-learning to reinforce best practices. The module was previewed by Rachel Blount and Laura Guardi, both representing Pharmig.
Rachel Blount and Laura Guardi presenting a new interactive training video.
Rachel Blount and Laura Guardi presenting a new interactive training video.
Brexit and regulations
Andrew Hopkins gave a second presentation addressing a concoction of topics, from ways to produce pharmaceutical grade water (reverse osmosis or distillation) to Brexit (the impact of regulations on making medicines in the U.K.) His central theme was, however, Good Manufacturing Practice (GMP) and the forthcoming changes to the guidance for sterile products (Annex 1 to European Union GMP). The new guidance foster the need for a formal microbial contamination risk assessment.

The take-home messages from the conference, chaired by GlaxoSmithKline expert microbiologist David Keen, were that more can be done to protect patients in the production of safe medicines. For this, quality risk management and new technologies are the tools required to achieve this.

Written by Dr. Tim Sandle

Monday, 8 January 2018

Microbiological Aspects of Cleaning Validation


Cleaning validation refers to the methodology applied to give the assurance that a cleaning process has removed residues and contaminants from a piece of equipment or machinery. Residues may be microorganisms; active pharmaceutical ingredients; other process chemicals, such as buffers; cleaning agents themselves (such as detergents); or microbiological culture media (in relation to aseptic process simulations). Assurance relating to cleaning validation refers to both the effectiveness of the cleaning process and the consistency at which cleaning is applied. As with any other type of validation, the ‘validation’ aspect refers to providing documented evidence that that the acceptance criteria have been met.

Tim Sandle has written a new paper. Here is an extract:

Cleaning is assessed based on the level of residues that remain, either those directly found on the equipment or those indirectly contained within the final rinse after water has passed through or over the equipment. Whether the residues remaining have been reduced to a satisfactory low level is based on predetermined acceptance criteria (2). The levels need to be sufficient low to ensure that the next product manufactured is not compromised by waste or contamination from the previous product (that is in ensuring that cross-contamination does not occur). An additional concern is with the microbial bioburden.

With equipment cleaning, this can be undertaken using an automated process (such as CIP - Clean-in-Place technologies) or manually (which often involves the physical removal of the equipment and its transport to a wash-bay; sometimes called COP - Clean-Out-of-Place). In general manual cleaning should be avoided due to process and operator variability. Where manual cleaning cannot be avoided, due to technical limitations, robust controls need to be in place to ensure consistency.

The chemical verification of cleaning validation is relatively well described. What is often less clear, and some contentious in terms of whether it needs to always be included, is the microbiological aspect. Important to the microbiological aspect are microorganisms themselves (a direct hazard) and the presence of residues that potentially provide a microbial growth source, should contamination be present or contamination occur during the hold period (an indirect hazard).

To evaluate these microbiological risks a sound microbiological sampling plan is required. The emphasis on sampling is important since microorganisms cannot be introduced into the process. This is unlike a chemical assessment where equipment can be deliberately soiled with a residue to test out cleaning efficacy. Microbial controls should not be introduced into the cleaning process. This article assesses the risks from microorganisms and the cleaning requirements necessary to achieve microbial control.



The reference is:

Sandle, T. (2017) Microbiological Aspects of Cleaning Validation, Journal of GxP Compliance, 21 (5): 1-12, at: http://www.ivtnetwork.com/article/microbiological-aspects-cleaning-validation

To find out more please contact Tim Sandle at: pseudomonas@btinternet.com  

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