Importance of Microbial Contamination Control

Tim Sandle has written an editorial of the special edition of the Journal of GxP Compliance, dedicated to pharmaceutical microbiology.

This special edition captures some of the current themes and issues relating to pharmaceutical microbiology and contamination control, and many of the points required to develop a control strategy.

The importance of microbiological control in relation to the manufacture of pharmaceutical and healthcare products is the theme of this special compilation for IVT Network. The articles selected highlight the twin themes of maintaining control through the assessment of risk and the use of sound, scientific methods to assess risk. This latter area includes the use of rapid and alternative methods.

While microbiology plays a role in drug development, through the application of biotechnology (including the development of anti-infective agents and with the manufacture of pharmaceutical products), a considerable part of the role of the pharmaceutical microbiologist is with protecting pharmaceutical and healthcare products from spoilage by microorganisms and thus protecting patients and consumers. With both sterile and non-sterile products, the effects can range from discoloration to the potential for fatality.

The reference is:

Sandle, T. (2018) Editorial: Importance of Microbial Contamination Control, SPECIAL EDITION: Essential Microbiology for GXP Compliance: 3-6 - http://www.ivtnetwork.com/article/essential-microbiology-gxp-compliance 

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Disinfectant Efficacy Testing for Fungi on Non-Porous Surfaces: A Case Study

An important aspect of the selection and evaluation of disinfectants is the disinfectant qualification programme. After a disinfectant has been chosen based on its chemical properties and expected performance/effectiveness, each disinfectant should be assessed to ensure its efficacy (and for European Medicines Inspectorate and U. S. FDA regulated premises this is mandatory). Efficacy is demonstrated through performance testing to show that the disinfectant is capable of reducing the microbial bioburden in either suspension (planktonic state) or from cleanroom surfaces to an acceptable level. The disinfectant efficacy validation should provide documented evidence that the disinfectant demonstrates bactericidal, fungicidal, and/or sporicidal activity necessary to control microbial contamination in the facility. This chapter summarises the test requirements and the different standards that are currently available.

A new paper of interest:

Regulatory agencies expected the users of disinfectants within cleanrooms to evaluate the efficacy of disinfectants. Various standards are available to guide the microbiologist through this process. What is more difficult is the content of some of the standards themselves because they have not been written specifically for the healthcare sector or the pharmaceutical industry (more typically they have evolved from the food, cosmetics or environmental control sectors). It may be necessary for the microbiologist to adapt the standards to suit practical situations (backing this up with a well-thought out rationale). Another point to be considered before embarking on such validation is whether all of the standards are to be replicated or whether experimental work required by some of the standards can be provided by the manufacturer of the disinfectants.

Given that most regulators and microbiologists regard the surface test as the most meaningful of the laboratory methods, this paper addresses this test. This paper outlines and approach taking for the assessment of a disinfectant to kill fungi on a surface. Of the different disinfectant efficacy studies, surface studies are generally regarded as the most challenging and representative of actual cleanroom conditions. For this, one organism is used as an example – the fungus Cladosporium, which as presented here was an environmental isolate from a pharmaceutical cleanroom. Cladosporium is one of the most commonly detected fungi from the as-built environment.

Surface tests, however, are not straightforward. The approach presented here is based on European surface test requirements; while other approaches differ slightly, the overall methodologies are similar. Hence the approach here can be used as a case study for others to evaluate against.

The reference is:

Sandle, T. (2018) Disinfectant Efficacy Testing for Fungi on Non-Porous Surfaces: A Case Study, Journal of GxP Compliance, 22 (4): 1-12

For details see: Disinfection

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Webinar: In Vitro Pyrogen Detection, the new trend

Want to know more about in vitro Pyrogen detection? Find out about our new Monocyte Activation Test ready-to-use kit. Discover the benefits of the PyroMAT™ System, learn how to use it and go through a real-life case study.

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Make the move to the monocyte activation test—the only method that detects the full range of endotoxin and non-endotoxin pyrogens and contributes to the reduction of animal consumption for testing purposes.

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Pharmaceutical Microbiology Resources

Webinar: Best Practices for Cleaning and Disinfection of Cleanrooms and Disinfection Validation

Cleaning and disinfection of cleanrooms is of great importance as part of a contamination control strategy. For this to be effective, correct disinfectants need to be selected, rotation between biocides must in place, a sporicidal agent needs to be selected, disinfectants need to be qualified cleaning frequencies need to be established, and appropriate training given. This is hampered by the lack of a global approach to satisfy regulatory agencies. This webinar provides an overview of the focal points required to achieve a global approach for cleanroom disinfection.

Webinar details:

Date: Thursday, 18 October 2018 | Time: 10:00 AM PDT, 01:00 PM EDT | Duration: 60 Minutes

Presenter: Dr. Tim Sandle, see: https://www.onlinecompliancepanel.com/webinar/Global-Best-Practices-for-Cleaning-and-Disinfection-of-Cleanrooms-and-Disinfection-Validation-505381

Points covered:

• What is cleaning and disinfection?
• How to select disinfectants?
• Global guidelines for disinfection in cleanrooms
• EU GMP (& draft Annex 1), USP <1072>, FDA aseptic processing guidance, PIC/S
• How to use disinfectants effectively
• Points for success
• Approaching disinfectant validation: Differences between European and U.S. standards
• Practical approach to disinfectant validation: what is best for pharma?Legal requirements for disinfectants: Europe and U.S.

For further information see: Online Compliance Panel

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

PyroMAT™ System: Have you heard about the latest solutions for pyrogen detection?

PyroMAT™ System: Have you heard about the latest solutions for pyrogen detection?

The PyroMAT™ system is the only cell-line based Monocyte Activation Test (MAT) provided as a ready-to-use kit on the market: a new solution for sensitive, robust, and easy-to-perform pyrogen test

Make the move to the monocyte activation test—the only method that detects the full range of endotoxin and non-endotoxin pyrogens and contributes to the reduction of animal consumption for testing purposes.

Want to know more about our solutions? Join our live webinar on October the 25^th and find out more about the new PyroMAT™ System.

Register today

EDQM publishes a new section dedicated to biotherapeutics

As public standards for the quality of medicines in Europe, the monographs and reference standards of the European Pharmacopoeia (Ph. Eur.) play a major role in ensuring the quality of biotherapeutics, thereby contributing to overall patient safety. By providing these recognised common standards for the quality of medicines and their components, the Ph. Eur. promotes public health and ensures the safety of medicines for patients. Ph. Eur. Standards are designed to meet the needs of all stakeholders, including industry, Official Medicines Control Laboratories (OMCLs) and regulatory authorities.

The new biotherapeutics section on the EDQM website summarises Ph. Eur. Commission activities and achievements in this field. In addition to clarification of the role of Ph. Eur. monographs in the biosimilars regulatory pathway, it describes the recently concluded P4-BIO pilot phase and the ongoing pilot phase on monoclonal antibodies (“MAB pilot phase”), explaining the strategy followed by the Ph. Eur. when setting requirements for the quality of this important class of biotherapeutics. It also describes various levels of flexibility integrated into Ph. Eur. texts, including those introduced recently to address the structural complexity, heterogeneity and compound diversity derived from different manufacturing processes of complex biotherapeutics.

See EDQM: https://www.edqm.eu/sites/default/files/press_release_epd_biotherapeutics_and_new_tg_june_2018.pdf

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

How soil bacteria munch on plastics

Thin mulch films made of polyethylene are used in agriculture in numerous countries, where they cause extensive soil contamination. Researchers have now identified an alternative: films made of the polymer PBAT biodegrade in soils.

Our world is drowning in a flood of plastic. Eight million tons of plastic end up in the oceans every year. Agricultural soils are also threatened by plastic pollution. Farmers around the world apply enormous amounts of polyethylene (PE) mulch films onto soils to combat weeds, increase soil temperature and keep the soil moist, thereby increasing overall crop yields.

After harvest, it often is impossible for farmers to re-collect the entire films, particularly when films are only a few micrometers thin. Film debris then makes its way into the soil and accumulates in the soil over time, because PE does not biodegrade. Film residues in soils decrease soil fertility, interfere with water transport and diminish crop growth.

Researchers at ETH Zurich and the Swiss Federal Institute of Aquatic Science and Technology (Eawag) have now shown in an interdisciplinary study that there is reason to be hopeful. In their recent study, they demonstrate that soil microbes degrade films composed of the alternative polymer poly(butylene adipate-co-terephthalate) (PBAT). Their work has just been published in the journal Science Advances.

In their experiments, the researchers used PBAT material that was custom-synthesised from monomers to contain a defined amount of the stable carbon-13 isotope. This isotope label enabled the scientists to track the polymer-derived carbon along different biodegradation pathways in soil.

Upon biodegrading PBAT, the soil microorganisms liberated carbon-13 from the polymer.

Using isotope-sensitive analytical equipment, the researchers found that the carbon-13 from PBAT was not only converted into carbon dioxide (CO2) as a result of microbial respiration but also incorporated into the biomass of microorganisms colonizing the polymer surface.

The researchers are the first to successfully demonstrate -- with high scientific rigor -- that a plastic material is effectively biodegraded in soils.

Because not all materials that were labelled "biodegradable" in the past really fulfilled the necessary criteria. "By definition biodegradation demands that microbes metabolically use all carbon in the polymer chains for energy production and biomass formation -- as we now demonstrated for PBAT," says Hans-Peter Kohler, environmental microbiologist at Eawag.

The definition highlights that biodegradable plastics fundamentally differ from those that merely disintegrate into tiny plastic particles, for instance after exposure of the plastic to sunlight, but that do not mineralise.

In their experiment, the researchers placed 60 grams of soil into glass bottles each with a volume of 0.1 litre and subsequently inserted the PBAT films on a solid support into the soil.

After six weeks of incubation, the scientists assessed the extent to which soil microorganisms had colonised the PBAT surfaces. They further quantified the amount of CO2 that was formed in the incubation bottles and how much of the carbon-13 isotope the CO2 contained. Finally, to directly demonstrate the incorporation of carbon from the polymer in the biomass of microorganisms on the polymer surfaces, they collaborated with researchers from the University of Vienna.

At this stage, the researchers cannot yet say with certainty over which timeframe PBAT degrades in soils in the natural environment given that they conducted their experiments in the lab, not in the field. Longer-term studies in different soils and under various conditions in the field are now needed to assess the biodegradation of PBAT films under real environmental conditions.

See:

Michael Thomas Zumstein, Arno Schintlmeister, Taylor Frederick Nelson, Rebekka Baumgartner, Dagmar Woebken, Michael Wagner, Hans-Peter E. Kohler, Kristopher McNeill, Michael Sander. Biodegradation of synthetic polymers in soils: Tracking carbon into CO2and microbial biomass. Science Advances, 2018; 4 (7): eaas9024 DOI: 10.1126/sciadv.aas9024

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

New PIC/S Guidance Documents

The following new PIC/S Guidance documents have been adopted:

PIC/S Aide-Memoire on “CrossContamination in Shared Facilities” (PI 043- 1).

The purpose of this Aide-Memoire is to assist GMP inspectors in the assessment of the risks to the product from cross-contamination in shared facilities. This document provides guidance for GMP inspectors to use in preparation for, and performance of, inspections. It promotes a risk-based approach.

PIC/S Guidelines on the formalised risk assessment for ascertaining the appropriate GMP for excipients of medicinal products for human use (PI 045-1).

PIC/S Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities (PI 046-1).

PIC/S Guidelines on the principles of GDP for active substances for medicinal products for human use (PI 047-1).

Also, the following Chapters and Annex of the PIC/S GMP Guide have been revised:

• Chapter 3 on “Premises and Equipment”;
• Chapter 5 on “Production”;
• Chapter 8 on “Complaints and Product Recall”;
• Annex 17 on “Real Time Release Testing and Parametric Release”.
• The revised Chapters are based on the equivalent Chapters of the EU GMP Guide with some minor differences in terms of language.

See PIC/S: https://www.picscheme.org/en/news?itemid=51

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

GMP in Practice: Regulatory Expectations for the Pharmaceutical Industry

The fifth edition of the book "GMP in Practice: Regulatory Expectations for the Pharmaceutical Industry" is now available, at a special introductory price. 

The book is written by James Vesper and Tim Sandle. As companies strive to harmonize global requirements for quality systems, the 5th edition of this text provides an overview of the 34 essential global cGMP requirements that are typically included in a modern pharmaceutical quality system, including data integrity and how they have evolved. Explore risk-related questions, delve into several expectations for each quality system element encompasses, and review real-world examples from cGMP regulations from the US FDA, Health Canada, the European Union, the World Health Organization, and the International Conference on Harmonization (ICH). See: https://store.pda.org/ProductCatalog/Product.aspx?ID=4511

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

ISO 14644 - The Revised Standard and Implications for Cleanrooms (webinar)

The international standard for cleanrooms has undergone a major revision. This webinar discusses the revisions in the context of global GMPs and the overall contamination control strategy. The webinar discusses testing approaches and the assessment of test data. The learning point is with keeping cleanrooms compliant.

New webinar - Date: Thursday, 30 August 2018 | Time: 10:00 AM PDT, 01:00 PM EDT | Duration: 60 Minutes

Learn:

• How to assess a cleanroom as built, at rest and in operation
• How cleanroom standards inter-link to global GMPs
• How to evaluate cleanroom data
• How to assess cleanroom contractors
• The importance of a risk based approach
• Assessing microbial and particulate risks

This presentation will review the changes to ISO 14644 Parts 1 and 2 and will focus on the factors to consider when performing your risk assessment and creating your monitoring plan. How do justify sampling locations for classification? How often are you going to perform period reclassification? What about the other ancillary cleanroom testing required in ISO 14644-3? How often will you perform that based on risk? What items should you include in your monitoring plan document? Changes to these ISO standards will impact the way you perform cleanroom classification activities. Everything you need to know to be compliant to the changes.

See: Online Compliance Panel (https://onlinecompliancepanel.com/webinar/ISO-14644-The-Revised-Standard-and-Implications-for-Cleanrooms-509318)

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Pharmig News #72

A new edition of Pharmig News has been issued. In this edition:

• Pharmig events update
• Review of Pharmig Irish conference and risk management by Tim Sandle
• Brexit uncertainty by Tim Sandle
• Latest regulatory news
• And more!

Copies will have been sent to member organisations. To see a copy, please email Pharmig at: info@pharmig.org.uk

Tim Sandle's articles in this edition are:

Sandle, T. (2018) Microbiology Risk Management (QRM): a practical approach meeting, Pharmig News, Issue 72, pp2-4

Sandle, T. (2018) Brexit uncertainty for pharmaceutical companies, Pharmig News, Issue 72, pp5-6

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

New technical specification for auditors of ISO 45001

News from ISO:

ISO 45001, Occupational health and safety management systems – Requirements with guidance for use, made standardization history when it was published in March this year. Now, a new complementary technical specification – ISO/IEC TS 17021-10 – has just been published, defining the required skills and knowledge of those bodies auditing organizations that have implemented the health and safety standard.

ISO/IEC TS 17021-10, Conformity assessment – Requirements for bodies providing audit and certification of management systems – Part 10: Competence requirements for auditing and certification of occupational health and safety management systems, is intended to guarantee a harmonized approach to the accreditation of an ISO 45001 certification.

The new technical specification is aimed at auditors, or anyone making certification decisions related to ISO 45001, and will ultimately serve certification, accreditation and regulatory bodies by confirming that auditing and certification decisions related to ISO 45001 have been carried out by those who have the competence to do so.



Posted by Dr. Tim Sandle

Artificial Intelligenсe to Improve Cancer Diagnosis in NHS

British Prime Minister Theresa May is expected to challenge the National Health Service, health charities and artificial intelligence developers to work to together in order to transform how chronic diseases are diagnosed. Commentary by Tim Sandle.

Artificial Intelligenсe to Improve Cancer Diagnosis in NHS by Tim Sandle on Scribd

3-D structure of 1918 influenza virus

Virus-like particles (VLPs) are protein-based structures that mimic viruses and bind to antibodies. Because VLPs are not infectious, they show considerable promise as vaccine platforms for many viral diseases, including influenza. Realizing that fine details about influenza VLPs were scant, a team of researchers who specialize in visualizing molecular structures developed a 3D model based on the 1918 H1 pandemic influenza virus. They say their research, which appears online in Scientific Reports, could benefit VLP vaccine projects, targeting a range of viruses from HIV to Ebola and SARS coronavirus. The research was conducted by scientists at the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Other researchers had produced VLPs for 1918 H1 influenza that successfully protected animals from different influenza viruses. The NIAID group prepared hundreds of such VLP samples and analyzed their structure with a technique called cryo-electron microscopy, which quick-freezes samples with glass-like clarity. They then sliced through those VLP 3D structures -- like slicing through a loaf of bread -- to analyze their internal structure, using computers to document the size and placement of key molecules. After averaging all their data, the group then created a 3D 1918 influenza VLP model.

The scientists found that about 90 percent of the VLPs are hemagglutinin (HA) proteins (by weight) found on the VLP surface. In contrast, HAs comprise less than half of the viral proteins of natural influenza viruses. The number and location of HA molecules may influence the efficacy of VLP vaccines, influencing the binding of antibodies to specific epitopes on the HA protein. Those antibodies can similarly bind live influenza viruses, preventing them from infecting cells.

The research group, in NIAID's Laboratory of Infectious Diseases, is continuing its work by comparing its VLP data to data from other natural influenza viruses. They believe the more that is understood about the molecular organization of influenza VLPs, the better scientists will be able to develop effective seasonal and universal influenza vaccines.

See: Dustin M. McCraw, John R. Gallagher, Udana Torian, Mallory L. Myers, Michael T. Conlon, Neetu M. Gulati, Audray K. Harris. Structural analysis of influenza vaccine virus-like particles reveals a multicomponent organization. Scientific Reports, 2018; 8 (1) DOI: 10.1038/s41598-018-28700-7
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Diagnostic connectivity to combat antimicrobial resistance

The British government has entered into a partnership with FIND, a global non-profit dedicated to accelerating the development of diagnostic tests for diseases. This is to introduce digital technologies to combat the antimicrobial resistance problem.

The partnership, following the signing of a Memorandum of Understanding, establishes a three-year project focusing on connecting data from patients’ diagnostic test results into various national antimicrobial resistance surveillance program in low- and middle-income countries. This digital information will be to help address the rising problem of drug resistant infections.

The announcement about the collaboration was made on May, 22 2018 at the 71st World Health Assembly, which took place in Geneva, Switzerland. The project is being funded from U.K. Government’s Global Antimicrobial Resistance Innovation Fund. Here the British state will work with the Foundation for Innovative New Diagnostics (FIND).

The aim of the project, for the connectivity for diagnostics, is to improve worldwide surveillance of antimicrobial resistance. Here FIND and partner bodies will produce alternative tools and new solutions to connect information from antimicrobial resistant-related diagnostic testing of patients and to input the analyzed information into national surveillance programs operating in low- and middle-income countries. The aim is to greatly extend the scope of existing programs so they include routine hospital and community data.

The growing menace of antibiotic resistance presents the single most significant threat faced by the global population. The urgency is with profiling patterns of resistance, so that epidemiological patterns can be assessed, and with the development of new antibiotics. The risk is very real: human populations face the very real risk of a future without antibiotics. The implications of this are that life expectancy could fall due to people dying from diseases that are readily treatable today. For example, around 700,000 deaths each year are caused by drug-resistant pathogens worldwide.

The FIND strategy is that diagnostics plays an important role in helping to minimize the proliferation of drug-resistant bacteria, viruses, parasites and fungi. By using appropriate diagnostic tests, medical professionals can identify disease-causing pathogens and use this information to determine the presence of drug resistance. This is only possible through comprehensive databases, assessed using big data analytics.

An example is with drug resistant tuberculosis, here FIND are helping to develop better tests for case detection & drug susceptibility testing (sputum); improved tests for detection and triage (non-sputum); and latent-to-active prediction tests. These are often alternatives to lengthy culture based methods, offering rapid microbiological alternatives aimed at improved accuracy and faster time-to-result.

According to Catharina Boehme, who is the CEO of FIND: “Diagnostics are critical to tracking and monitoring diseases and the spread of drug resistance…Connecting diagnostics to surveillance systems at various levels from local to global will allow surveillance to be strengthened in LMICs – where the burden of infectious diseases is highest but data are currently limited.”

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology