EU GMP Annex 21

Annex 21 to the EU-GMP Guidelines has been published as a draft (on 20^th March 2020), titled "Importation of medicinal Products".

The Annex is aimed at Manufacturing and Importation Authorisation holders (MIA holders) who import human or veterinary medicinal products from third countries.

The Annex does not cover products that do not have a marketing authorisation in the EU/EEA and are directly re-exported.

The Annex includes:

·         Physical transfer from the third country to the EU/EEA

·         Certification by the Qualified Person (QP) (link with the requirements of Annex 16)

·         Requirements for equipment and facilities

·         Required documentation

·         GMP requirements for manufacturers and exporters in third countries

·         Qualification and audits under the responsibility of the importing company and the Qualified Person (QP)

·         Import testing

·         Contractual regulations between all companies or persons involved in the import

For details, see: https://ec.europa.eu/health/sites/health/files/files/gmp/importation_medicinalproducts_draftannex21_en.pdf

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Knowing more about a virus threat may not satisfy you

People who rate themselves as highly knowledgeable about a new infectious disease threat could also be more likely to believe they don't know enough, a new study suggests.

In the case of this study, the infectious disease threat was the Zika virus. But the authors of the new study, published recently in the journal Risk Analysis, say the results could apply to the recent novel coronavirus (COVID-19) outbreak.

"The Zika virus and the coronavirus have important things in common," said Shelly Hovick, co-author of the study and assistant professor of communication at The Ohio State University.

"In both cases, they are shrouded in uncertainty and have received a lot of media attention. Our research looks at how people seek and process information when there is so much uncertainty."

One of the key findings of the new study: With limited information about Zika available, more knowledge was not that comforting.

"We found that the more people thought they knew, the more they realized they didn't know enough," said Austin Hubner, lead author of the study and a doctoral student in communication at Ohio State.

"With the Zika virus, even the experts themselves didn't know much at the time. That's the same thing we're seeing with the coronavirus, and that's scary for people who believe they are at risk."

For the study, the researchers conducted an online survey of 494 people of childbearing age living in Florida in December 2016.

See:

Austin Y. Hubner, Shelly R. Hovick. Understanding Risk Information Seeking and Processing during an Infectious Disease Outbreak: The Case of Zika Virus. Risk Analysis, 2020; DOI: 10.1111/risa.13456

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Guide to sterility test isolators

An isolator is an arrangement of physical barriers that are integrated so that the workspace (an enclosed environment) within the isolator is sealed from the outside environment. Isolators provide a testing environment free from contamination, through routine sanitization using a validated cycle and confirmed by environmental monitoring.

In addition, these devices enable the isolation between the operator and the process. There are many complications with isolators, from design to qualification, and with general operation.

It certainly remains that isolators cannot prevent contamination caused by GMP deficiencies such as poor aseptic procedures and inadequate training of operators.

To address these concerns and to outline best practices, Tim Sandle has written a new Pharmig guide:

Sandle, T. (2019) Guide to sterility test isolators, Pharmig, Stanstead Abbotts: UK (ISBN 978-0-9560804-9-3)

Foe details see: https://www.pharmig.org.uk/en/products/publications/

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Antimicrobial resistance bacteria found in raw pet food

The fight against antimicrobial resistance has a new problem – raw pet food, according to new research. Sales of biologically appropriate raw food, especially for dogs, have risen in recent years.

Microbiologists working in Switzerland have assessed 51 samples of raw diet pet food, drawn from different suppliers in stores as well as from the Internet. The analysis revealed that some three-quarters of the food samples contained bacteria that has the potential to trigger gastrointestinal infections limits.

Furthermore, over half of the foods that tested were found to contai bacteria that are resistant to antimicrobials, meaning that such organisms are hard to kill. Among the bacteria were certain strains of Escherichia coli. Some bacteria can produce the enzyme extended-spectrum beta-lactamase (EBSL), which can enable these microorganisms to resist the impacts of antibiotics.

Other pathogens that have been isolated from raw pet food includes Campylobacter spp, Clostridium spp, enterotoxigenic Staphylococcus aureus, Listeria monocytogenes, and Salmonella spp.

According to lead researcher Dr. Magdalena Nuesch-Inderbinen: “It is really worrying that we found EBSL-producing bacteria in over 60 percent of samples.”

The new research highlights a new area of concern in the battle against antimicrobial resistance. Antimicrobial resistance is a phenomenon the occurs naturally as bacteria respond to various pressures within the environment. What is of concern is the worldwide acceleration of resistance. U.S. Centers for Disease Control and Prevention (CDC) data finds that many high-income countries are entering a “post antibiotic era.”

One reason for the trend is linked to the practice of animal feed-additive antibiotic usage, which is some countries is an integral part of animal-production technology. The reason for adding of antibiotics is for the creation of 'leaner' meat (animals given antimicrobial tend to grow more quickly). In addition, the indiscriminate administering of antibmicrobials to animals is a way of side-stepping putting in place better animal hygiene conditions.  Many countries have banned this practice, but it also continues in many other parts of the world.

The study additionally highlights concerns for pet owners when considering to buy raw food and then how that food is handled in the home.  In fact, the American Veterinary Animal association “discourages the feeding to cats and dogs of any animal-source protein that has not first been subjected to a process to eliminate pathogens because of the risk of illness to cats and dogs as well as humans.”

The research findings have been reported in the journal Royal Society Open Science.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Integrating Good Distribution Practice into the QMS

Good Distribution Practice (GDP) concerns the distribution processes for pharmaceutical products that results in medics and patients obtaining access to the medications required. For the pharmaceutical organization, the distribution process occurs both upstream and downstream. Upstream are the suppliers who create goods and services used in a manufacturer’s own operations, such as raw components or materials. The downstream supply chain efficiently distributes a company’s products or services to its customers. Each stage, both upstream and downstream, needs to be proactively managed to minimize quality, as well as financial, confidentiality, operational, reputational and legal risks.

Tim Sandle has written a chapter for the book GoodDistribution Practice: A Handbook for Healthcare Manufacturers and Suppliers.

Here is an extract:

These distribution processes concern supply chain, including cold supply chains (where required), and the tracking and tracing of medicines. Traceability includes ensuring that the required environmental controls are met, and that tampering or fraudulent activities are avoided, to the level that each induvial item can be traced from the completion of manufacture to its arrival with the end user (Marucheck et al, 2011). The distribution network for medicinal products is invariably complex and it involves many different parties at different stages. In addition to the challenges associated with this complexity and with protecting the product from being affected by environmental conditions, damage, or loss, there is also a threat from criminal activities centered on seeking to introduce falsified medicines into the supply chain (Bruinsma, and Bernasco, 2004).

GDP requirements are designed to codify and to structure the processes. These requirements bear close similarity to the requirements set out in Good Manufacturing Practice (GMP) regulations. The primary difference is that GDP covers the wholesale distribution of medicines, whereas GMP covers their manufacture.  There overlap between the two rest with the need to maintain product quality after a batch has been released from the manufacturing site, as well as the necessity to monitor and control complaints, address problems, and have a system in place to enact a recall.

In assessing the requirements for GDP, there are different national and supranational standards. In the US GMP is based on the Code of Federal Regulations 21 CFR 210/211, with additional guidance contained within USP chapter 1079 “Good Storage and Distribution Practices for Drug Products.” (USP, 2018) There is an additional USP chapter of interest, chapter 1197 “Good Distribution Practices for Pharmaceutical Excipients” (USP, 2018b). For Europe GDP is based on the Directive of the Board of the European Community 92/25/EEC regarding the wholesale distribution of drugs for human consumption, supported by guideline 2015/C 95/01 (European Commission, 2015), and the Falsified Medicines Directive (European Commission, 2011), which requires a unique identifier and an anti-tampering device to allow the verification of the authenticity of medicinal products. With the World Health Organization, the applicable text is Annex 5 of the WHO recommendations “good distribution practices for pharmaceutical products.” (WHO, 2010a) One commonality through these regulations and following on from items raised during pharmaceutical organization inspections, is with a focus on serialization. This has required for new strategies, processes, and technologies that allow for a business to, at any time, pinpoint the location and origin of any single drug.

A weak GDP system is one where there is a key disconnect between the manufacturer and the process that occurs once the product leaves the facility (Rees, 2013). An overarching area of regulatory concern is with the effectiveness of the incorporation of GDP into the Quality Management System (QMS), a system that applies for both wholesaler and broker. This chapter looks at Quality Risk Management in relation to GDP, covering areas like good distribution principles, the necessity of having Quality Technical Agreements in place, and measures to take appropriate corrective and preventative actions should deviations occur.

The reference is:

Sandle, T. (2019) Integrating Good Distribution Practice into the QMS. In Schmitt, S. (Ed.) Good Distribution Practice: A Handbook for Healthcare Manufacturers and Suppliers, Volume 1, DHI/PDA Books, River Grove, IL, USA, pp241-272

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Four-level food web for gut microbes discovered

A new computational model suggests that the food web of the human gut microbiome follows a hierarchical structure similar to that of larger-scale ecosystems.

In the human gut, hundreds of species of microbes exchange nutrients in a complex food web. Large-scale food webs, such as those of tropical forests, typically follow a hierarchy in which energy flows from plants, to herbivores, to carnivores. Wang and colleagues wondered if the gut microbiome could be considered to follow a similar hierarchy, from microbes that consume nutrients in food eaten by the human host, to those that eat nutrients produced by the first microbes, and so on.

To address this question, the researchers developed a computational model that uses the known species of microbes in a person's gut to predict microbial metabolites -- the substances the microbes generate as part of their biological activities, and which may serve as nutrients for other gut microbes. The metabolite predictions generated by the model are in line with experimental data, providing support for its accuracy.

The new model indeed predicts a four-level hierarchy for the food web of the gut microbiome. This suggests that species composition systematically changes along the length of the gut. Near the entrance to the lower gut, one might find bacteria from the highest hierarchical level -- those that consume nutrients in food eaten by the human. Near the end of the gut, one might find bacteria from the lowest level.

The researchers are now working to refine their model by using a machine-learning approach to infer important competitive relationships between gut microbes. Doing so could improve the model's accuracy, potentially reducing the need for expensive measurements of metabolic profiles in research on gut function.

Journal Reference:

Tong Wang, Akshit Goyal, Veronika Dubinkina, Sergei Maslov. Evidence for a multi-level trophic organization of the human gut microbiome. PLOS Computational Biology, 2019; 15 (12): e1007524 DOI: 10.1371/journal.pcbi.1007524


Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Ancient feces reveal how 'marsh diet' left Bronze Age Fen folk infected with parasites

New research published today in the journal Parasitology shows how the prehistoric inhabitants of a settlement in the freshwater marshes of eastern England were infected by intestinal worms caught from foraging for food in the lakes and waterways around their homes.

The Bronze Age settlement at Must Farm, located near what is now the fenland city of Peterborough, consisted of wooden houses built on stilts above the water. Wooden causeways connected islands in the marsh, and dugout canoes were used to travel along water channels.

The village burnt down in a catastrophic fire around 3,000 years ago, with artefacts from the houses preserved in mud below the waterline, including food, cloth, and jewellery. The site has been called "Britain's Pompeii."

Also preserved in the surrounding mud were waterlogged "coprolites" -- pieces of human faeces -- that have now been collected and analysed by archaeologists at the University of Cambridge. They used microscopy techniques to detect ancient parasite eggs within the faeces and surrounding sediment.

Very little is known about the intestinal diseases of Bronze Age Britain. The one previous study, of a farming village in Somerset, found evidence of roundworm and whipworm: parasites spread through contamination of food by human faeces.

The ancient excrement of the Anglian marshes tells a different story. "We have found the earliest evidence for fish tapeworm, Echinostoma worm, and giant kidney worm in Britain," said study lead author Dr Piers Mitchell of Cambridge's Department of Archaeology.

"These parasites are spread by eating raw aquatic animals such as fish, amphibians and molluscs. Living over slow-moving water may have protected the inhabitants from some parasites, but put them at risk of others if they ate fish or frogs."

Disposal of human and animal waste into the water around the settlement likely prevented direct faecal pollution of the fenlanders' food, and so prevented infection from roundworm -- the eggs of which have been found at Bronze Age sites across Europe.

However, water in the fens would have been quite stagnant, due in part to thick reed beds, leaving waste accumulating in the surrounding channels. Researchers say this likely provided fertile ground for other parasites to infect local wildlife, which -- if eaten raw or poorly cooked -- then spread to village residents.

"The dumping of excrement into the freshwater channel in which the settlement was built, and consumption of aquatic organisms from the surrounding area, created an ideal nexus for infection with various species of intestinal parasite," said study first author Marissa Ledger, also from Cambridge's Department of Archaeology.

See:

Marissa L. Ledger, Elisabeth Grimshaw, Madison Fairey, Helen L. Whelton, Ian D. Bull, Rachel Ballantyne, Mark Knight, Piers D. Mitchell. Intestinal parasites at the Late Bronze Age settlement of Must Farm, in the fens of East Anglia, UK (9th century B.C.E.). Parasitology, 2019; 1 DOI: 10.1017/S0031182019001021

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Audit and Control for Healthcare Manufacturers (book)

Aufit book 2.pdf by Tim Sandle on Scribd

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Audit and Control for Healthcare Manufacturers: A Systems-Based Approach

Compliance is an affirmative indication or judgement that the supplier of a product or service has met the requirements of the relevant specifications, contract or regulation; also the state of meeting the requirements. Compliance is something that meets both the text and the spirit of a requirement. A key way to assess compliance is through auditing. For further details, see the PDA Bookstore: https://www.pda.org/bookstore/product-detail/5014-audit-and-control-for-healthcare-manufacturers

Audit and Control for Healt... by Tim Sandle on Scribd

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Happy New Year!

I'd like to wish all readers a Happy New Year and all the best for 2020!



Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Mycoplasma Conference Summary

For further details see: Roche

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Happy Holidays!

I'd like to wish all readers of Pharmaceutical Microbiology all the best wishes for the Holiday season!

Thank you for supporting this website and our LinkedIn and Facebook groups.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Microbiology Roundtable

American Pharmaceutical Review has run another in its Microbiology Roundtable features. Here is an extract from Tim Sandle:

Q. In general, what are some of the current critical issues/trends facing pharmaceutical manufacturers in regards to microbiology testing and remediation?

Sandle:  One of the biggest issues is with time-to-result, which is affected by the (largely) continued dependency upon culture-based methods and which is symptomatic by the slow take-up of rapid microbiological methods. Being able to obtain data faster, enables better responses.

While rapid methods will undoubtedly help, it remains that contamination control and good design are the most important considerations. There is little value testing if a given process has not been correctly designed to minimize the ingress of contamination, Of the different routes in, the main one remains people and the way they behave. Be it sterile or non-sterile manufacturing, designing systems and putting in place barriers to reduce the opportunity for personnel to get close to the product are paramount.

The reference is:

Microbiology Roundtable (2019) Michael Reynier, Jordi Iglesias, Tony Cundell, Suzanne Williams, Frank Panofen, Paula Peacos, Tim Sandle, Quinton Inglet, Jonathan Swenson, American Pharmaceutical Review, pp86-91

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology

Digital transformation of pharmaceuticals - what's new?

Here is my article on digital transformation of pharmaceuticals - "Becoming Pharma 4.0: How Digital Transformation Is Reshaping Pharmaceuticals".

The digital transformation of biopharmaceutical manufacturing is continuing at a rapid pace as companies attempt to mine the sources of data available. Innovations include predictive analytics, big data analytics, and creating the digital plant. Digital transformation offers a mechanism to revise its business model, to improve production processes, to design new drugs faster by using artificial intelligence to screen compounds and to increase responsiveness to customers. Furthermore, the volume of data processed by pharmaceutical firms shows no sign of slowing down. This means pharmaceutical companies must act quickly in terms of building core internal digital capabilities and moving beyond their traditional IT functions to all areas of the business.

See : https://www.biopharmatrend.com/post/109-becoming-pharma-40-how-digital-transformation-is-reshaping-pharmaceuticals/

Good Distribution Practice: A Handbook for Healthcare Manufacturers and Suppliers

An excellent new two-volume book has been published, vital for those working in pharmaceuticals and healthcare:

Good Distribution Practice: A Handbook for Healthcare Manufacturers and Suppliers - Edited by Siegfried Schmitt.

A two-volume reference publication, discussing in detail global regulations and practices. Over 30 professionals and experts share their knowledge, interpret the regulations and provide a plethora of best-practice examples.

Volume 1
Following an introduction into the subject of Good Distribution Practice (GDP), the key topics covered in this volume relate to:

• The applicable GDP regulations globally, including serialization
• Qualified Person (QP) and Responsible Person (RP) in GDP
• GDP as part of the Quality Management System (QMS)
• Good Distribution Practice - the industry perspective
• GDP Checklist

Volume 2

Following an introduction into the subject of Good Distribution Practice (GDP), the key topics covered in this volume relate to:

• De-risking the supply chain
• Serialisation and Packaging in Practice
• Other chapters provide details about packaging materials. 

The authors not only introduce the readers to the options available, but more importantly help assure that the selection of packaging materials is linked to shipping routes, pharmaceutical material properties and lastly costs. 

The book is available from the PDA Bookstore:

PDA - Volume 1

PDA Volume 2

Or from Amazon :

Volume 1

Volume 2

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology