Wednesday 30 September 2020

Phenotypic analysis of the unstimulated in vivo HIV CD4 T cell reservoir


Measuring the levels of proteins in the immune cells of people receiving anti-retroviral drugs to treat HIV reveals which of these cells the virus is hiding in.

There is no cure for the human immunodeficiency virus infection (HIV), but anti-retroviral drugs allow infected people to keep the virus at bay and lead a normal life. These drugs suppress the growth of HIV, but they do not eliminate the virus. If the treatment is interrupted, the virus bounces back within weeks in most individuals. HIV can start growing again because it hides within particular immune cells, called T cells. These infected cells stay in the infected person’s body for their whole life in a dormant or “latent” state, and represent the main barrier to an HIV cure. If these cells could be eliminated or prevented from producing more virus without daily treatment, then HIV could be cured. The fact that HIV hides inside T cells has been known for a long time, but it has remained unclear exactly what kinds of T cells the virus prefers.

One challenge to characterizing latently-infected cells is that there is no single protein made by them that is not also made by uninfected T cells. The latently-infected T cells are also very rare: HIV mainly attaches to a protein called CD4, but only one in about a million T cells with CD4 contain the virus. To figure out which CD4-carrying T cells in a patient sample are latently infected, the cells are extracted from the patient’s body and ‘reactivated’ so the virus will start growing again. Unfortunately, the mixture of drugs used to reactivate the T cells changes the cells and the proteins they are producing, which obscures the features the latently-infected T cells had before reactivation.

Neidleman, Luo et al. developed a new approach to trace the infected, reactivated T cells back to their state before reactivation. Using computational methods and a laboratory technique called mass cytometry, the levels of approximately 40 different proteins were measured in millions of T cells from people living with HIV. These experiments provided an ‘atlas’ of overall T cell features onto which each reactivated cell could be mapped. The population of latently-infected T cells exhibited common features among all the participants. Selecting a few of the most abundant proteins on the surface of the latently-infected cells allowed these cells to be physically separated from all other immune cells.

In the future, this relatively pure population of infected T cells could be used to study how HIV can persist for many decades. The ‘map’ of these cells’ features will provide a valuable resource for HIV researchers and might enable the discovery of new drugs to eliminate the latent T cells.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Tuesday 29 September 2020

Is two metres social distancing really enough?


Social distancing is one of they key measures to take when seeking to minimize the risk of coronavirus transmission. The generally accepted safe distance is two-metres. But is this enough? New research sheds doubt.

The most effective way to avoid coronavirus transmission is to stay away, but that's not really practical in modern society. According to World Health Organization (WHO) advice (as reported in The Lancet), social distancing (sometimes, and more accurately, called physical distancing') is the next most important thing a person can practice to avoid coronavirus.
This is followed by regular hand washing – using hot water and soap or an alcohol based hand sanitizer - and lastly by wearing a face mask. Social distancing is about observing a set distance apart from another person and avoiding all forms of physical contact such as hugs and handshakes. 
The general advice is that 2 meters (or 6 feet) guidance works, this is the medical consensus (as Digital Journal reported earlier). This is because two meters is generally is outside of the range of droplet projection. In terms of the effectiveness of the distance, at one metre, the chance of becoming infected by someone with COVID-19 is 13 percent; whereas, at two metres, this drops to 3 percent
While social distancing works, not everyone in society is predisposed to practice it. With this, there are some demographic variations, with social distancing more likely to be followed by seniors compared with younger people, as a consumer survey conducted by Bospar indicates. But is two metres enough? A new study titled “Viable SARS-CoV-2 in the air of a hospital room with COVID-19 patients“ suggests that a safe distance might need to be 5 metres. 
This hospital-based study looks for viable virus particles. By sequencing the genome of the virus University of Florida researchers found and showed that it came from that patient and not some other source. The patient was identified as having active respiratory infection with a nasopharyngeal swab positive for the coronavirus - SARS-CoV-2. 
What is most of interest is that the virologists detected viable virus up to 4.8 metres away from the patient. This is over twice the recommended 2 metres (6 foot) spacing recommended by most governments. The genome sequence of the SARS-CoV-2 strain isolated from the material collected at this distance was identical to that isolated from the nasal swab from the patient with an active infection. This finding also adds weight to the aerosol transmission route (and not just a cough or a sneeze), which currently divides scientific opinion.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Monday 28 September 2020

Effectivity of HEPA Filters to Remove Viruses from Air Entering Cleanrooms

In the manufacture of certain pharmaceuticals, viral removal or destruction is a key part of manufacturing (such as products produced from cell lines or from blood or plasma, as per ICH Q5A). This requires a combination of viral secure areas and viral removal steps. In a previous American Pharmaceutical Review article, this author examined the ways by which viruses can be removed or inactivated from pharmaceutical products (including solvent-detergent; low pH inactivation; heat; chromatographic separation; and nanofiltration).

In terms of detection, nucleic acid-based assays such as Polymerase Chain Reaction (PCR) and Next Generation Sequencing (NGS) provide rapid and sensitive detection of adventitious and endogenous viruses in constituent materials and finished products. This follow-up article considers how viruses can be excluded by HEPA filtration, thereby minimizing the entry of viruses and viral particles into cleanrooms. Aspects of this review may also be of interest in the wider context of the 2019-2020 novel coronavirus pandemic (caused by the virus SARS-CoV-2).

In relation to this, Tim Sandle has written an article:

Sandle, T. (2020) Effectivity of HEPA Filters to Remove Viruses from  Air Entering Cleanrooms, American Pharmaceutical Review, 23 (4): 56-58 (

Viral contamination is a potential safety threat common to all animal- and human-derived biologics and it follows that ensuring virological safety is challenging. Contamination of the production system can occur, and the processes of viral removal are complex and require regular assessment (to avoid the incomplete inactivation or removal of viruses). A further challenge arises with creating viral secure areas. As well as the control of materials and personnel, and important factor in maintaining such an area is through effective air filtration.

For further details, please contact Tim Sandle.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Saturday 26 September 2020

Travel was a major factor with coronavirus spread

The extent to which coronavirus spread was based on the type and speed of the interventions taken. In many cases, such interventions were effective. However, key networks were also responsible for the viral spread.

New research finds that early interventions undertaken in most parts of Europe and the U.S. were effective at reducing coronavirus infections. yet in certain areas there was a viral spread. These networks for transmission are drawn out from epidemiological models coupled with travel records.

The types of data analyzed included flight records and the total number of COVID-19 cases collated from various global regions in January and February 2020. More detailed information about different strains of the SARS-CoV-2 virus were also added into the analysis, such as comparing the different genomes of virus sampled from infected individuals. A focus was with determining the extent to which these viral samples were related to each other (what is known as phylogenetics).

As an example, the researchers have shown how the dispersal of the virus from China to the U.S. was via British Columbia, Canada, located just north of Washington State. After some viral infection cases were established in Canada, sometime around February 1, 2020, it then spread from Canada to the U.S. This challenges earlier theories that the main infections were originated from a Chinese national flying into Seattle from Wuhan, China.

With Europe, the data analysis suggests that the origin was on January 20, 2020,when a businessman working for an automotive supply company in Bavaria, Germany, flew in for a business meeting from Shanghai, China.

The findings into these sustained transmission networks can offer clues for fighting a second wave of viral transmission or for when a new health threat emerges. This is based on the strength of the model, which is based on computer programs that are capable of simulating the complex epidemiology and evolution of the coronavirus.

The research has been published in the journal Science, with the paper titled "The emergence of SARS-CoV-2 in Europe and North America."

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Wednesday 23 September 2020

Covid-19 Impact On Global Telemedicine Market

Rapidly Growing Telemedicine has Investors on their Heels

A guest post by Tanay Bhalla

The concept of telemedicine has evolved in recent years. As people are demanding easier ways to avail medical treatment and diagnosis, there have been several advances in telemedicine. Telemedicine is a method that involves providing clinical services through a distance. Through telemedicine, the user doesn’t necessarily have to be present at the hospital or clinic and can avail medical consultation through the comfort of his home. Earlier, telemedicine was used for treating people in remote places as well as people who could not afford or access modes of hospital visits. But as time progressed and telemedicine systems advanced, analysts were able to unfold the true potential held by these systems. With increasing applications across diverse industries, the global telemedicine market will be worth $185 billion by the end of 2026.

Cloud Access and Smartphones Have Laid a Collaborative Foundation for Telemedicine

As the number of smartphone users has risen significantly in the past decade, almost all computer-operating software are being integrated into mobile OS as well. The advancements in smartphones have been exceptional, so much so that people would now prefer to have a smartphone that would do the work of a computer, rather than using the actual computer. Technology has played a key role in the recent surge in the adoption of smartphones. Cloud integration is among the long lists of benefits offered by smartphones. Cloud integration, combined with the availability of fast data networks among many regions in the world, has opened up a broader scope of advancements for telemedicine. Could-integrated systems enable the elimination of a locally installed physical drive. These factors significantly reduce the cost and space associated with the functioning of telemedicine.

‘Remote Patient Monitoring’ Among the Key Benefits Offered by Telemedicine Services

Telemedicine allows medical examination and consultation of patients residing almost anywhere in the world. With minimal operational pre-requisites, telemedicine services offer massive benefits such as improved efficiency, faster diagnosis, precise medication, and consultation. Remote patient monitoring is one of the primary benefits of telemedicine. Through video-enabled platforms, doctors or related personnel can interact with the patient residing almost anywhere in the world. Concepts such as constant monitoring and updates allow more frequent consultation. Patients do not necessarily have to travel longer distances again and again. These benefits save a huge amount of time and money, which would have been much higher in cases of hospital visits. Patients who are bed-ridden and physically disabled can benefit hugely from remote patient monitoring. As a result, telemedicine services are gaining more popularity in the coming years.

Hesitancy is the Main Reason Behind the Surge in Telemedicine Use During Covid-19 Pandemic

The coronavirus outbreak has created a sense of urgency and panic among people across the world. While people are understandably being advised to stay indoors, healthcare professional and researchers have registered a state of urgency. Nonetheless, people are becoming hesitant to consult doctors for normal consultation at clinics and hospitals, mostly due to the contagious nature of the disease. Yet again, technology has delivered the answer a human obstacle. The advent of telemedicine has helped consumers consult doctors through video communication apps. Through telemedicine, doctors can prescribe medicines and other remedies through the comfort of his home. While the pandemic is set to last for a while, companies are targeting this sector for short-term business plans.

Besides remote patient monitoring, telemedicine possesses several other benefits. The main reason behind the rise of the telemedicine industry is the flexibility and comfort that it offers. The advances in telemedicine largely favor geriatric population. Additionally, people who cannot afford services such as hospital visits, high costs of in-hospital stays, and on-the-stop doctor consultation will also contribute to the growing popularity of telemedicine.

A few of the other benefits offered by telemedicine include:

· Reimbursement policies

· Flexibility in scheduling doctor consultation

· Improved access to care

· Reduced administrative tasks

· Patient tracking and monitoring

· Cases of natural disasters

Telemedicine Holds Massive Potential in Disaster Management

The use of telemedicine is not just limited to bed-ridden patients. Events such as natural disasters hold a huge potential for telemedicine and telemedicine consultation services. In cases of floods, earthquakes, and other disasters, it is difficult for people to travel to the hospital or even consult doctors in clinics, for that matter. Moreover, natural disasters such as tsunamis leave people exposed to viral diseases. The chances of epidemics are higher during these events. In such cases, telemedicine can help people avail medical services at the comfort of their homes and avoid outdoor hospital visits. This helps in reducing the risks associated with infections and epidemic diseases. With technology at the fore of several telemedicine services, there is a significant rise in the efficacies associated with these services.

As Telemedicine Are Gaining Popularity, Diverse Healthcare Markets to Open Up As telemedicine is growing in popularity, investors are likely to hover around. Telemedicine will open up several markets in the healthcare industry, pertaining to nurses, insurers, therapists, and physicians. The advances in technologies, backing from governments, high investment, and a growing R&D emphasis will all contribute to the development of telemedicine in the forthcoming years.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Tuesday 22 September 2020

Using a public restroom? Mask up!

Think you don't need to worry about COVID-19 while using a public restroom? A group of researchers from Yangzhou University in China recently reported that flushing public restroom toilets can release clouds of virus-laden aerosols for you to potentially inhale and flushing urinals does likewise.


The researchers tracked virus-laden particle movements when urinals are flushed.


The researchers' work clearly shows public restrooms can be dangerous places for potentially becoming infected from a virus, especially during the COVID-19 pandemic. Other work has shown that both feces- and urine-based virus transmission is possible.


Flushing a urinal, much like flushing a toilet, involves an interaction between gas and liquid interfaces. The result of the flushing causes a large spread of aerosol particles to be released from the urinal. This has been simulated and tracked.


What the simulations revealed is disturbing. The trajectory of the tiny particles ejected by flushing a urinal manifests an external spread type, with more than 57% of the particles traveling away from the urinal.  When men use urinals within a public restroom, these tiny particles can reach their thigh within 5.5 seconds when compared to the toilet flush, which takes 35 seconds to reach slightly higher. Particles from urinals also show a more violent climbing tendency.


Urinals are used more frequently within densely populated areas, and the researchers point out that particles will travel faster and farther, which poses a serious public health challenge.



This work underscores how important it is to wear a mask within public places but especially restrooms.




Ji-Xiang Wang, Yun-Yun Li, Xiang-Dong Liu, Xiang Cao. Virus transmission from urinals. Physics of Fluids, 2020; 32 (8): 081703 DOI: 10.1063/5.0021450

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Monday 21 September 2020

Application Of Wireless Technology In The Pharmaceuticals Sector

With wireless technology becoming more popular in the pharmaceutical sector, this brings with the convenience the joint risks of cybersecurity and data integrity.

To look into both issues, Tim Sandle has written a new article.

Data collected from the pharmaceutical plant can be held on computerized systems, servers or portable media; it can also be traveling through wired or wireless networks. At any location, data is always at risk from intentional and unintentional breaches, together with problems arising from intermittent connections, lost data, and security risks. In addition, problems can arise due to inappropriate selection of technology or with poor configuration, such as: Poorly characterized or poorly utilized wireless systems (e.g., wireless networks). Lost, corrupted, or time-delayed transmissions, and degradations.

The reference is:

Sandle, T. (2020) Application Of Wireless Technology In The Pharmaceuticals Sector: Maintaining Data Integrity, Security And Privacy, Journal of GxP Compliance, 24 (3):

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Sunday 20 September 2020

Yeast strain makes fatigue-fighting ornithine

Researchers from the Nara Institute of Science and Technology and the Nara Prefecture Institute of Industrial Development have revealed that a mutant strain of sake yeast produces 10 times the amount of the amino acid ornithine compared with the parent yeast strain.

Ornithine is a non-protein-making amino acid and a precursor to two amino acids -- arginine and proline. It has been found to perform several physiological functions, such as reducing fatigue and improving sleep quality.


To find ethanol-tolerant yeast strains, the researchers isolated mutants that accumulated proline, which can alleviate ethanol toxicity, using a conventional mutagenesis (i.e., one that doesn't involve genetic modification). They also conducted whole genome sequencing analysis, and performed brewing tests with sake yeast strains. Then they identified and analyzed a new mutation in a gene that encodes a variant of N-acetyl glutamate kinase that increases intracellular ornithine level.


The results of this study will contribute to the development of improved yeast strains for production of high levels of ornithine, and the strain obtained in this study could be readily applied to sake, wine, and beer brewing. Ornithine-accumulating yeast strains could also be used in the production of ornithine-rich dietary supplements made from these yeasts and their products.




Masataka Ohashi, Ryo Nasuno, Shota Isogai, Hiroshi Takagi. High-level production of ornithine by expression of the feedback inhibition-insensitive N-acetyl glutamate kinase in the sake yeast Saccharomyces cerevisiae. Metabolic Engineering, 2020; 62: 1 DOI: 10.1016/j.ymben.2020.08.005

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Saturday 19 September 2020

Microbiome's role in attacking cancerous tumors

Researchers have discovered which gut bacteria help our immune system battle cancerous tumors and how they do it. The discovery may provide a new understanding of why immunotherapy, a treatment for cancer that helps amplify immune response, works in some cases, but not others.


The findings show combining immunotherapy with specific microbial therapy helps the immune system to recognize and attack cancer cells in three forms of cancer.


The researchers identified bacterial species that were associated with colorectal cancer tumours when treated with immunotherapy. Working with germ-free mice, they then introduced these specific bacteria along with immune checkpoint blockade, a type of cancer immunotherapy. Research revealed that specific bacteria were essential to the immunotherapy working. The tumours shrank, drastically. For those subjects that did not receive the beneficial bacteria, the immunotherapy had no effect.




Lukas F. Mager, Regula Burkhard, Nicola Pett, Noah C. A. Cooke, Kirsty Brown, Hena Ramay, Seungil Paik, John Stagg, Ryan A. Groves, Marco Gallo, Ian A. Lewis, Markus B. Geuking, Kathy D. McCoy. Microbiome-derived inosine modulates response to checkpoint inhibitor immunotherapy. Science, 2020; eabc3421 DOI: 10.1126/science.abc3421

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Friday 18 September 2020

Biological Product Inspections During COVID-19

The FDA has issued a new guidance document titled “Manufacturing, Supply Chain, and Drug and Biological Product Inspections During COVID-19 Public Health Emergency Questions and Answers”.

FDA plays a critical role in protecting the United States from threats such as emerging infectious diseases, including the Coronavirus Disease 2019 (COVID-19) pandemic. FDA is committed to providing timely guidance to support response efforts to this pandemic. FDA has issued this guidance to provide answers to frequently asked questions about regulatory and policy issues related to inspections, pending drug applications, and changes in manufacturing facilities for approved pharmaceutical products.

The document can be accessed here:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Thursday 17 September 2020

Release of sterile products – looking at the focal points

There are numerous risks and regulatory requirements that must be considered to ensure appropriate contamination control of sterile medicinal products. Tim Sandle discusses the complexities of sterility assurance and provides guidance for manufacturers to ensure that appropriate risk management processes are in place.

In relation to this, Tim Sandle has written an article for European Pharmaceutical Review. The article can be accessed here.

Sterile products manufacturing has the added complexity that the final product needs to be sterile (absent of viable microorganisms and microbial by-products, such as bacterial endotoxin). Especially given that sterility cannot be conclusively tested (the sterility test, while mandatory of aseptically filled products and some terminally sterilised products is inherently flawed; not least because not all microorganisms in the environment are culturable and there is no universal means to grow them). Therefore, there is reliance upon a robust sterility assurance system. The person tasked with batch release must be aware of the risks centred on the release of contaminated product to the market and associated risks of patient harm.

The reference is:

Sandle, T. (2020) Release of sterile products – looking at the focal points, European Pharmaceutical Review, 25 (04): 6-11

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Wednesday 16 September 2020

EMA Guideline on the quality of water for pharmaceutical use

The EMA Guideline on the quality of water for pharmaceutical use

EMA/CHMP/CVMP/QWP/496873/2018 adopted by CVMP for publication on 18 June 2020; it will be effective 010 February 2021

This guideline replaces the Note for guidance on quality of water for pharmaceutical use (CPMP/QWP/158/01 EMEA/CVMP/115/01) and CPMP Position Statement on the Quality of Water used in the production of Vaccines for parenteral use (EMEA/CPMP/BWP/1571/02 Rev.1).

The note for guidance has been updated to reflect the following changes in the European Pharmacopoeia:

• revised monograph for Water for Injections allowing the possibility to use methods other than distillation for producing water of injectable quality;

• new monograph for Water for preparation of Herbal drug extracts

• suppression of the monograph for Water, highly purified

The guideline has also been updated to reflect current expectations for the minimum acceptable quality of water used in the manufacture of active substances and medicinal products for human and veterinary use.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Tuesday 15 September 2020

Draft Annex 21 - Importation of Medicinal Products

New Annex with currently no deadline for implementation.


The Annex weighs heavily on referencing Annex 16 “ for further guidance on QP” although no new responsibilities have been defined. It also draws on the other Chapters of the Eudralex Vol4 in a similar manner.

Key points:

  • The Annex seeks to clarify or further detail terminology used, for example importation
  • Annex 16 – Importation is not defined as such whereas
  • Annex 21 states ” the term importation refers to the action of physically bringing medicinal product, from outside the territory of EEA/EU what implies the necessity of clearing it into the customs territory of an EU/EEA state QP certification of a batch of medicinal product takes place after physical importation and custom clearance.”
  • Or there are semantic differences in wording between Annex 21 and Annex 16 with same intent, for example
  • Annex 21 Section 2.4: “The Qualified Person certifying the batch has to ensure that all the medicinal products for human or veterinary use that are imported into the Union from a third country were manufactured in accordance with EU GMP or equivalent standard and tested in the Union, unless there are appropriate arrangement in place between the Union and the third country (e.g. Mutual Recognition Agreement or ACAA). See also Annex 16 for further guidance.
  • Annex 16 Section 1.5.4: “The QP certifying the finished product is responsible for ensuring that each finished medicinal product batch has been manufactured in accordance with GMP and the MA. Unless an MRA or similar agreement is in place between the EU and the exporting country, the QP is also responsible for ensuring that the finished medicinal product batch has undergone in a Member State a full qualitative analysis, a quantitative analysis of at least all the active substances and all the other tests or checks necessary to ensure the quality of medicinal products is in accordance with the requirements of the MA.”

Other issues:

  • (2.1) The sites which have specific responsibilities for importation in relation to the medicinal product or imported dosage form are
  • (i) Site of Physical Importation
  • (ii) Site of QP certification of Imported medicinal products.
  • The above importation responsibilities must be carried out by entities appropriately authorised under a MIA.
  • (2.5) Testing in an EU/EEA state covers all the tests needed to demonstrate that the medicinal product meets the specifications that are set out in the marketing authorization. – Annex 16 only refers to testing and does not contain this clarification.
  • (2.6) Written agreements should be in place between the site(s) performing manufacturing, importation activities and the MAH, as appropriate, in accordance with Chapter 7 of the EU GMP.
  • Chapter 7 does not contain this clarity and Annex 16 only mentions “agreements between sites”
  • 3. Pharmaceutical Quality System
  • 3.1. The site(s) conducting importation activities should have an appropriately detailed documented Pharmaceutical Quality System in accordance with Chapter 1 of the EU GMP Guide and reflecting the scope of the activities carried out.
  • 3.2. Product Quality Reviews should be performed by the site performing QP certification for the products imported, including products imported for export.
  • Written agreements should be in place to define the relative responsibilities of the MAH, the importer(s) and the third country manufacturers, as appropriate, in relation to compiling of the Product Quality Reviews as outlined in Chapter 1 of the EU GMP.
  • In addition to the PQR requirements described in Chapter 1, where sampling of the imported product is conducted in a third country in accordance to Annex 16, then the PQR should include assessment of the basis for continued reliance on this sampling practice. PQRs should also include a review of deviations relating to transportation. Specific requirements for sampling and transportation of imported products are detailed further in Annex 16.
  • As part of this review, the analytical results from importation testing should be compared with those in the Certificate of Analysis generated by the third country manufacturer. Any trends or discrepancies should be documented and investigated.
  • Transportation and Sampling are not stated within Chapter 1 (1.10)
  • (4.2) Imported medicinal products should be stored under quarantine after receipt, until their release for further processing or following QP certification or confirmation as appropriate, in accordance with Annex 16. Segregated areas should exist for quarantined products. Any system replacing the physical quarantine should give equivalent security.
  • Whereas Annex16 states - Until a batch is certified, it should remain at the site of manufacture or be shipped under quarantine to another site which has been approved for that purpose by the relevant Competent Authority.
  • (5.1.2) The site of physical importation should have, at minimum, details of transportation and receipt of the product (see also Annex 16).
  • Annex 16 does not detail this as such.
  • (5.1.3) 5.1.3.Relevant purchasing and delivery documentation should be available for inspection at MIA holder responsible for QP certification and clearly indicate:
  • The site from which the product has been dispatched (the origin of the product).
  • The site of physical importation.
  • Shipping details (including, transportation route and temperature monitoring records) and customs documentation, as applicable.
  • (5.5) Where batches have been subdivided and the individual quantities imported separately, documentation confirming reconciliation of the quantities should be made available at the site where QP certification takes place. Any discrepancy should be investigated.
  • (6.1) The manufacturing site where QP certification occurs should ensure that an ongoing stability program is in place, as required in Chapter 6. The ongoing stability program may be carried out at a third country site as an outsourced activity provided that the QP has all the necessary information to assure ongoing product quality. Details of the ongoing stability program, such as protocols, results and reports should be available for inspection at the MIA holder responsible for QP certification.
  • (6.2.) The QP certifying the batch is responsible for ensuring that, where required, the safety features have been affixed to the packaging.
  • (7.1) Adequate provisions should be in place between the site(s) performing importation activities, the third country manufacturer and the MAH for handling complaints, quality defects and product recalls as required in Chapter 8 of the EU GMP Guide. This should be defined in contractual arrangements.
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Monday 14 September 2020

Recalls of Pharmaceutical Products: Eliminating Contamination and Adulteration Causes

Tim Sandle has published a new book - Recalls of Pharmaceutical Products: Eliminating Contamination and Adulteration Causes.

Are you prepared for recalls relating to pharmaceutical and healthcare medications and medical devices? This book contains details about recalls from start to finish, including advice on how to handle a recall and, more importantly, how they can be avoided. Read about regulatory perspectives, trends and primary causes for product recalls, notable recalls and lessons, quality metrics, and supply chain risk management. You can also find relevant information designed to help about labels, packaging, data integrity, methods to ensure GDP, and other industry best-practices.

For details see:

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Sunday 13 September 2020

Microbiology Roundtable

American Pharmaceutical Review has run a 'Microbiology Roundtable' and I was invited to take-part.

Here is an extract:

Question: Looking back at the last year, what are some critical industry issues affecting efforts to detect and eliminate microbiological contaminants?

Sandle: There has been some interesting developments with microbial detection technology. As with most technological waves, developments spring from outside of the pharma sector and then become adopted later (such is the conservative nature of our sector).

It’s clear that we need platforms for rapid detection and characterization of microbial agents are critically needed to prevent and respond to contamination issues. The advancement of such technologies can help, at last, for microbial methods to fit in with the process analytical technology paradigm.

I think the area that will grow fastest is with monitoring pharmaceutical water systems for microbial contamination. This includes miniaturized biomolecular techniques and real-time monitoring systems, taking the form of online meters, such as ATP-metry and flow cytometry.

As such instruments develop, so do the key operational metrics like speed to results, identification depth, reproducibility, and multiparametricity.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

Saturday 12 September 2020

4 Ways to Filter Water for the Pharmaceutical Industry

For pharmaceutical manufacturers, filtration is an essential process. Water is a key ingredient in a massive range of pharmaceuticals — from pills to vaccines to inhalable solutions — and that water needs to be of a medicine-grade purity before it can be used. 

A guest post by Megan R. Nichols (STEM Writer)

There are several common approaches to water filtration that companies in the pharmaceutical industry use to ensure water purity. The particular pharmaceutical water system used, however, may change depending on a company's specific needs and the resources they have access to. Here are a few examples of the techniques they might employ: 

1. Single and Multiple Effect Distillation

Distillation is the use of evaporation to purify a liquid. It's how most desalination plants create drinking water from salt-filled seawater. In the pharmaceutical industry, three main types of distillation are used — single effect, multiple effect and vapor compression distillation.

Single and multiple effect distillation systems consist of numerous stages — anywhere from one to 14 — called effects. Unpurified water is fed into these effects, where it's heated by vapor in tubes, causing some of the water to evaporate. 

Microbiology book

The first effect occurs under extreme pressure. Each effect is a lower temperature and pressure than the last. Because the boiling point of water decreases as the pressure drops, it's possible to collect and use the vapor generated in one effect to boil water in the next. As a result, only the vapor in the first effect is generated by adding heat from an outside source to boil water.

As the vapor passes through the tubes, some of it cools and condenses into distilled water, which flows out of the system and is collected. 

Single and multiple effect systems are popular among pharmaceutical manufacturers for a few different reasons. They require few moving parts and use low power levels to create purified water. However, they can't be scaled down effectively. That means even the simplest effect distillation system takes up a significant amount of space, making them unworkable for smaller operations. 

2. Vapor Compression Distillation

Vapor compression distillation is distinct from multiple effect distillation but uses a similar process to create purified or drinking water. With a vapor compression system, heat is generated by putting water vapor under extremely high pressure levels. When the vapor is compressed, its temperature rises to the point where it can boil water.

This vapor is then passed into a reduced-pressure chamber, where it causes feed water to evaporate. The vapor produced by this process is removed from the chamber, cooled and then extracted from the system as distilled water.

Unlike multiple effect systems, vapor compression distillation works at smaller scales, making it practical for manufacturers that don't need to produce massive amounts of distilled water. However, vapor compression distillation does need significantly more power because electricity is required to keep the vapor hot and under high pressures. 

3. Ultrafiltration (UF)

Ultrafiltration is another approach that companies sometimes use in pharmaceutical water systems. With UF, manufacturers use one or more membranes to remove large molecules from water. The feed water is pumped into the system at high rates and under pressure, where it passes through a membrane filter or series of filters. The water, along with low-weight molecules — like soaps and salts — passes through, while macromolecules, typically oils and solids, are trapped by the membrane.

Because the membrane's pores are so small in size — around 0.01 microns — they can also capture microorganisms, like viruses and bacteria. Ultrafiltration is more effective at capturing unwanted compounds than microfiltration, but it's less effective than nanofiltration and reverse osmosis.

Ultrafiltration isn't typically used by itself, due to concerns that unwanted molecules will be left in the filtered water. However, using ultrafiltration first before another process, like reverse osmosis, helps to remove large molecules from the feed water that can damage more sensitive filters. 

4. Reverse Osmosis (RO)

Reverse osmosis, like ultrafiltration, is a filtration process that forces water through a membrane to strip out unwanted molecules and produce filtered water. The pore size in RO membranes is typically around 0.0001 microns but can be slightly larger in some applications. There is no widely used filtration method that uses stronger membranes.

The filters remove unwanted ions, molecules and microorganisms from feed water.

Because the filters used for reverse osmosis tend to be highly sensitive, reverse osmosis is typically not used by itself in a filtration process. In a case like this, before the water undergoes reverse osmosis treatment, the manufacturer will purify it with another approach — typically distillation or ultrafiltration. Reverse osmosis ensures extremely high-quality water. 

Filtered Water for Use in Pharmaceuticals

Purified water is an essential ingredient for many pharmaceuticals, meaning water purification technology is key to the pharmaceutical industry. Most manufacturers take advantage of a few popular methods. Various types of distillation, which use evaporation to separate water from solids, are common. Other approaches, like those that use filters to purify water, are also popular. However, the risk of damaging filters means that highly effective filtration systems — like reverse osmosis filtering — usually require additional pretreatment of feed water.

Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (


Friday 11 September 2020

The Contribution of Complementary and Alternative Medicine To Good Health

CAM practices have been around for centuries, and have been thought to provide a range of benefits for a multitude of physical and mental health issues. Let’s see what their appeal is for people…

Tis' the season to remain healthy, not only in body but also in mind. As we have seen coronavirus spread its wings across the globe, people have been advised to stay inside their homes, and only to come out when absolutely necessary. The virus has also overseen the crumbling of economies across the globe, with many people being put out of their jobs, which has led to severe mental stress among the population. We all know that the mind and the body need to complement each other effectively in order to support overall health, and that any disturbance in one will have a telling effect on the other. In this context, along with the growing discussions around the vaccines that have been in development for quite a while now, there have also been suggestions regarding the repurposing of 'complementary and alternative medicines' through rigorous testing and research.

Put simply, the concept of complementary and alternative medicine has been around for a long long time, and have been generally considered safe to practice by the general population, although the scientific and medical communities have been skeptical of these practices. However, this scenario is gradually changing, with experts supporting the integration of traditional practices into the modern setup. Although the terms are used as one, there is a major difference in the functioning of complementary and alternative techniques, with the former being used ALONGSIDE conventional treatment techniques, while the latter is used IN PLACE of conventional techniques. As the world grapples with a rising number of cancer cases, there has been a growing focus by a certain percentage of medical experts to recommend complementary therapies in the hope that it may help in the healing process, while improving the quality of life.

According to Johns Hopkins Medicine, CAM is widely practiced in the United States, with 38% of adults and 12% of children having had an experience with these therapies. Here, we will have a look at some of the most common CAMs.

1. Acupuncture - Comes under traditional form of alternative medicine, and is very widely known among the general population. It is a traditional Chinese healing technique that focuses on stimulating certain points of the body through the use of needles, with the aim to begin the natural healing process. Acupuncture has been found to be effective in combating widespread conditions such as neck and back pain, anxiety, depression, and infertility, among others.

2. Homeopathy - Is based on the belief that the body cures itself ("like cures like"). Practitioners make use of small amounts of natural substances such as plants, in order to get the healing process going. Homeopathy is used to 'treat' a number of ailments such as allergies and depression, along with a variety of common illnesses. Critics of this process cite the 'placebo effect' as the benefit of this technique, and scientists have stated that any medicine, in the absence of an active ingredient, as in this case, should not have any effect on the body. Still, the method has remained ever-so-popular.

3. Naturopathy - This practice tries to get to the root cause of a person's illness, instead of working out the symptoms. Naturopathy combines traditional treatment procedures with modern scientific concepts. Some of the common issues or illnesses that are supposed to be treated include headaches, obesity, allergies, and chronic pain and fatigue, among others. However, some of the treatment methods involved can affect your body negatively, which includes the use of supplements, as well as undertaking spinal adjustments and detox diet plans.

4. Ayurveda - This technique was developed more than 3000 years ago in India, and works on the concept of optimal balance between the mind, body and spirit. Ayurvedic practitioners believe that each person is made of 5 basic universal elements, which are space, air, fire, water and earth. Furthermore, this also involves the concept of Life forces, or 'doshas', with the three primary ones being Vata dosha, Pitta dosha and Kapha dosha. A proper balance between these three is the key to good health. Ayurveda has become very popular across the globe; however, in the US, the FDA has banned certain Ayurvedic medicines on the grounds that they contain toxic metals, which can prove to be extremely harmful for children. 

5. Yoga – Yoga is probably one of the most well-known healthy practice that has been attained crazy popularity around the globe, particularly in the modern age where time is at a premium and there has been a rapid adoption of the ‘fast-life’ culture. There are a number of yoga techniques that address a range of issues, and offer benefits such as increased flexibility, weight reduction, improved respiration and vitality, and enhanced circulatory health, among many others. This is one of the few complementary techniques that can be practiced irrespective of gender or age, and has benefits for every demographic. The 21st of June is celebrated as World Yoga Day across the globe.

6. Chakra Healing - This treatment technique has had a centuries old history, with the 'Chakra system' originating in India between 1500 and 500 BC in the Vedas. There are 7 chakras, with each corresponding to a specific organ, state of being and influence. These are the root chakra, the sacral chakra, the solar plexus chakra, the heart chakra, the throat chakra, the third-eye chakra, and the crown chakra. Even if one of these goes out of balance, it disrupts the whole system. Yoga and meditation instructors talk a lot about these chakras and how to effectively manage them, even though again, there is not enough solid evidence to back these claims and approach.

7. Kinesiology - Comes from the Greek word for the study of movement. It was started by a chiropractor, Dr. George Goodheart, later integrating conventional Chinese medicine techniques. The major principle of applied kinesiology is that 'a stress that strains the whole body may objectively manifest as a weakening of a single muscle. Kinesiology makes use of manual muscle testing to evaluate a patient's health, which helps in understanding the problem, be it in the physical, emotional or biochemical realm. Kinesiology provides best results when used in combination with conventional treatment techniques. Kinesiologists apply various techniques such as acupressure, lymphatic massage, flower therapy, myofascial releases, and meridian therapy, among others.

8. Magnetic Resonance Therapy – This treatment technique has garnered great interest among chiropractors; it involves the use of a low-level magnetic field that can be used for activating a particular cell and/or tissue area. The introduction of Magnesphere in this realm has furthered the growth of this technique. The operation involves the principles of biology and quantum physics, and comprises the elements of nuclear magnetic resonance, chronic stress, stimulation of the Vagus nerve, and heart rate variability (HRV).

These are just a few of the complementary and alternative techniques that have piqued the interest of the global population in the past few years, and helped in changing lives of millions. Even though many of these techniques have been looked down on by a certain section of medical professionals, the introduction and integration of technology has helped it in slowly gaining acceptance among the medical community. With the COVID-19 pandemic forcing people to stay at home, people have taken to online resources in order to carry out their health routines and regimen, especially Yoga. With physical and mental health becoming the most precious resource in these challenging times, there will undoubtedly be greater focus on CAM in the coming years.

A few other CAM techniques have been summarized below:



Tai Chi

A stress management technique that originated in China, it results in decreased stress, anxiety and depression, while improving energy and stamina, as well as enhanced flexibility.


A Japanese technique that promotes stress reduction, relaxation and healing, on the basis of the idea that the life fore energy of an individual needs to be high for a person to be healthy and happy.


A mind, body and spirit practice that integrates posture, breathing technique, movement, sound, self-massage, and focused intent. The National Qigong Association supports the development and promotion of this technique.


It is a trance-like state wherein the individual experiences heightened focus and concentration. This technique has been thought to be effective in coping with stress and anxiety, letting go of one’s fears, thus making them relaxed and calm.


One of the more popular and simple ways of stress management, deals with the mental aspect of health. Helps in reducing negative emotions, improving stress management, as well as increasing creativity, patience and tolerance.

Visualization and Guided Imagery

Another stress management technique, involves the creation of a detailed mental picture of an attractive or peaceful environment. Research has shown this practice can reduce anxiety and fear in individual, while also lessening the frequency of headaches.

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Thursday 10 September 2020

Timely publications from Jeanne Moldenhauer

As the numbers of Warning Letters and 483s have risen considerably recently, Jeanne Moldenhauer has done considerable research to bring you an incredibly useful analysis that will help you discover major causes of such letters thereby enabling you to avoid same.  

To view the full table of contents of each text and purchasing information click the links provided below each cover.
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (

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