Aseptic Process Simulations: A look at the essential features

Aseptic processing (image by Tim Sandle)

In terms of sterility assurance, aseptic processing is a more hazardous pharmaceutical process to conduct compared with terminally sterilised products since should microbial contamination occur during dispensing the product, due to its inherent nature, cannot be subjected to a post-filling sterilization process. With aseptic filling the product is sterilized separately, then filled and packaged using sterilized containers and closures in critical processing zones. Several environmental controls, particularly in relation to cleanroom and clean air design, are built into the process to protect the product. Personnel are required to follow strict discipline in relation to good aseptic techniques. One of the periodic assessments undertaken to measure the likelihood of non-sterility is the Aseptic Process Simulation (APS) test (or the ‘media simulation trial’).

By Tim Sandle

With media simulation trials, a microbiological growth medium is used in place of the product and filled as if it were a product under the ordinarily processed conditions. Media fills start at the beginning of filling operations (immediately after the line setup), during and after manipulations and interventions, and until the last vial has been filled. For conducting media simulation trials, regulatory guidance provides an outline of what needs to take place and the acceptance criteria (ideally zero growth in any filled container) that need to be adopted.

Learn about culture media for aseptic process simulations here.

The advantage of the media simulation trial over the sterility test is that all media-filled containers can be incubated. Following incubation they can be 100% visually inspected and checked for microbial growth. By this complete inspection, the contamination rate associated with a media fill can be assessed directly.

Media simulation studies are designed to simulate the entire process to evaluate the sterility and confidence of the process. Process simulation studies include formulation (compounding), filtration and filling with suitable media. Simulations are made to ensure that the regular process for product batches repeatedly and reliably produces the finished product of the required quality. To be of value, media trials must be representative of the types of products filled on an aseptic processing line. To ensure that media fills are representative, the fill must replicate the conditions under which product filling takes place, and they must be undertaken under "worst-case" conditions so as to provide a realistic challenge.

This article looks at the regulatory requirements for the APS, some of the design requirements and the importance of selecting an appropriate culture medium.

GMP logo (designed by Tim Sandle)

Regulations

The U.S. Food and Drug Administration states that the purpose of an APS is to qualify the aseptic process using a microbiological growth medium manipulated and exposed to the operators, equipment, surfaces, and environmental conditions similar to the way the product itself is exposed (FDA, 2004). In addition, EU GMP Annex 1 requires an APS to be capable of:

•    demonstrating the capability of the aseptic process to produce sterile drug products
•    qualifying aseptic processing personnel
•    reflecting typical aseptic operations

The core regulatory expectations are:

1.    For three initial qualifying (or repeat qualifying) media fills to be run per line.
2.    For media fills to be executed twice per year per line.
3.    For personnel to be qualified once per year through a media fill.
4.    For media fills to typically be 5,000 or 10,000 units.
5.    For media fills to be of sufficient length so that all inherent and corrective interventions can be performed.
6.    For media fills not to incorporate poor practices.
7.    For the acceptance criteria to be zero.

Therefore, APS studies should simulate aseptic manufacturing process operations as closely as possible, incorporating a worst-case approach.  The potential risks to be included are [1]:

•    personnel
•    equipment
•    components
•    facility and utilities

The main requirements for performing aseptic process simulations have become more demanding during the last decade; at the same time, the technologies used for aseptic compounding and filling have improved, providing greater protection (including simple-use items and barrier systems, including isolators).

Key considerations

The APS program should incorporate the contamination risk factors to allow an assessment of the state of process control to be made. In doing so, media fill studies should simulate aseptic manufacturing process operations as closely as possible, incorporating a worst-case approach. These include [2]:
 

Equipment

•    Factors associated with the longest permitted run on the processing line
•    Number and type of normal interventions, e.g., maintenance, stoppages, and equipment adjustments
•    Line speed and configuration
•    Lyophilization where applicable
•    Aseptic assembly of equipment (e.g., startup)

Personnel

•    Number of personnel and their activities
•    Shift changes, breaks, and gown changes
•    Operator fatigue

Cleanroom operator. Image by Tim Sandle

Operations

•    Number of aseptic additions
•    Number and type of aseptic equipment disconnect and connections
•    Aseptic sample of collection
•    Manual weight checks
•    Container closure system
•    Specific provisions for aseptic processing-related standard operating procedures

Media fill documentation should include the identification of the risk variables in defining the worst case. A protocol in the form of a batch record must be prepared for each run on each line.

Design of a media fill program should include, but is not limited to, the following:

•    Identification of the process  such as lyophilization, aseptic solid, powder and liquid fill,
•    Identification of the room,
•    Identification of the filling line and equipment,
•    Number of personnel to participate,
•    Identification of which personnel teams are to be included. Where filling runs normally include a shift change, then a shift change should be practised during the media filling run,
•    Type of container/closure to be used – should compare with routine production,
•    Line speed (to be equivalent to production operations, especially with the time that vials spend at the point of filling),
•    Number of units to be filled,
•    Number and type of interventions,
•    Type of culture media to be used,
•    Volume of medium to be filled into the containers (so there is sufficient headspace to permit microbial growth),
•    Aseptic set up and assembly of sterile equipment,
•    Incubator identification and incubation time and temperature,  
•    Environmental monitoring requirements (these should not be less stringent than those used in a product fill),
•    Copy of the batch record to be used,
•    Acceptance criteria for the test,
•    Description of documentation record for the final report,
•    Box or tray number of positive units,
•    Growth support testing requirements and results,
•    Rationale for worst-case ‘‘parameters’’ chosen (see below),
•    Summation of the data from the batch record environmental monitoring samples based upon this information, a conclusion is formulated regarding the acceptability of the manufacturing process and the facility.

The environmental monitoring performed during the media fill should be equivalent to the monitoring performed during a commercial product fill [3].

Matrix approach to design

When several different vial combinations, fill volumes, line speeds and so on are established for an array of different product fill combinations it is acceptable to design a matrix so that worst combinations can be selected and incorporated into the media fill program. The term "worst-case," in the context of media fills, is taken to be the combination of events and circumstances that could, in theory, expose a product (or, in this case, a product simulation) to the greatest chance of microbial contamination [4].

The factors to consider include vials that have the widest neck diameter (thereby providing a larger target for the deposition of contamination), fill speeds or fill volumes (that lead to vials remaining at the point of fill for the longest time), larger media fill runs (where the longest fills, that over time, could lead to a higher frequency of contamination events occurring), and the type and nature of personnel interventions (where the act of a person intervening into a critical zone poses a potentially high contamination risk; some interventions, due to their complexity or time taken to complete, pose a greater risk than others).

No single risk factor necessarily presents a "worst-case." However, one combination of factors will probably present a greater potential risk to a product than another combination and thus may be considered a greater risk and "worst-case". It is the argument of this paper that, by placing these factors into some form of matrix, the "worst-case" is easier to visualize and justify. Once the "worst-case" combinations have been found, it is possible to draw up a rationale for the selection of these conditions for the execution of scheduled media fills.

Culture media (designed by Tim Sandle)

The importance of culture media selection

An APS is usually conducted with a soybean casein digest medium. This can be either a base that is used to make a broth and which is then sterile filtered or a ready-to-use liquid medium (which is pre-filtered and in a presentation suitable for small volume fills).  Where there are concerns about transmissible spongiform encephalopathies in relation to animal-derived products, alternative media like vegetable peptone broth (made from pea flour) can be substituted. Similarly, media fill runs with anaerobic media (alternate fluid thioglycollate medium without agar) can be required if anaerobes are isolated from the environments and product samples.  

Not all culture media is of the same quality or suitable for use with a media fill. Important criteria for suitable media for an APS include [5]:

•    Sterile
•    Cold filterability
•    Solubility
•    Format (granulated media)

In considering these:

Sterility

Using a medium that has been pre-sterilized avoids the use of a medium that is contaminated and hence which could pose a challenge to the sterilizing filter. The sterilization process, typically gamma- or x-ray irradiation, should not affect the properties of the medium or affect microbial growth.

Cold filtration

Using a medium that requires heating to enable it to dissolve and for it then to cool to pass through a filter is not always practicable within manufacturing. In addition, the application of heat needs to be carefully applied otherwise the nutritive properties of the medium can be affected. Filterability is assessed in terms of the time taken for a given volume of media to pass through filters made of different materials (such as PES, nitrocellulose, PVDF etc.), without clogging or loss of flow characteristics.

Selecting a medium with cold filtration properties can help prolong filter life and reduce replacements, saving both time and expenditure.

Format

A base medium is typically available in powdered form. Whilst common, there are advantages to using media in a granulated form. These advantages result from the agglomerated larger particles and include reduced dust release and spread during preparation. This reduces health risks to operators and prevents environmental and cross-contamination. In addition, the lower generation of dust reduces deposits on equipment, and this also eases handling and cleaning.

Granulated forms also have longer shelf life and material stability compared with powders.

Solubility

In a busy manufacturing area, time spent waiting for media to dissolve is unproductive. Hence, using a medium with rapid and effective solubility reduces preparation time and effort. Granulation is a process that can improve solubility and accelerate the time taken to dissolve when compared to equivalent products in a power format. The filtered medium should be of a clear appearance.

In addition to the above, the method of transferring culture media into the facility must be conducive to good contamination control principles (such as with the medium being provided triple-wrapped by the supplier and with the user having a defined method for introducing the medium into the manufacturing area).

Bacterial growth (designed by Tim Sandle)

Incubation and growth promotion

Media fill evaluation units should be incubated for not less than 14 days at temperatures between 20°C and 35°C. Many firms adopt a two-temperature incubation schedule to incubate at 20-25°C for a minimum of 7 days followed immediately by incubation at a higher temperature range of 30-35°C for a total minimum incubation time of 14 days. Other incubation schedules should be based on supporting data.

To be GMP compliant, the selected culture medium should be demonstrated for the growth promotion test. The microorganism panel is often the one used for the sterility test, as per pharmacopoeia guidelines.  Some organizations include environmental isolates taken from the aseptic filling area by way of a more robust challenge. It is recommended that growth promotion is performed at the end of incubation in order to demonstrate that the incubation conditions were not detrimental to the growth of organisms. The selection of containers for testing should be performed in the manner of samples selected for sterility testing, that is randomly selected units equidistant through the batch. The method of performing growth promotion testing should be based on pharmacopeial guidance (such as using the organisms recommended for the sterility test qualification) and ISO 11133: 2014 [6] principles. It may be appropriate to increase the size of the test panel by including representative organisms based on a review of the manufacturing environment.  

If growth promotion testing fails, the media fill test is invalid and an investigation must be performed. The media trial should be promptly repeated.

Summary

The APS remains a critical exercise to be conducted by the manufacturers of aseptically filled products. This article has discussed several considerations. Arguably, the two areas of greatest importance are with the design (especially with the capture of ‘worst-case’ factors when selecting the appropriate line/product combinations: longest fill duration; widest container opening and longest exposure time of open container) and with ensuring that media of appropriate quality is selected (including the considerations of sterility, and granulation, filterability).

References

1.    Agalloco, J. and Akers. J.  Risk Assessment and Mitigation in Aseptic Processing,  3rd edition, CRC Press, 2016.
2.    Sandle, T. Designing Aseptic Process Simulations: The Time and Container Number Conundrum, Journal of GxP Compliance, 20. 1-12, 2016
3.    Cundell, A. Microbial Testing in Support of Aseptic Processing, Pharm. Tech. 56-66 (June 2004).
4.    Sandle, T., Leavy, C. and Needham, G. (2012). A Risk Matrix Approach for Media Simulation Trials, Journal of Validation Technology, 18 (4): 70-78
5.    Sandle, T. (2018) Microbiological Culture Media: A Complete Guide for Pharmaceutical and Healthcare Manufacturers, DHI/PDA, Bethesda, MD, USA, ISBN Number: 9781942911159
6.    ISO 11133:2014 Microbiology of food, animal feed and water — Preparation, production, storage and performance testing of culture media

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

AI-Driven Calibration Tools Are Transforming Sterility Assurance

Sensor. Image by Filya1 - Own work, CC BY-SA 3.0, https://commons.wikimedia.org/w/index.php?curid=6304562

New sensor technologies offer greater accuracy than ever when verifying sterility in pharmaceutical environments. However, issues like calibration drift stand in the way of that reliability. Even the most sophisticated monitoring tools can slowly become less precise over time. Calibration is the obvious solution, but it is not a foolproof process, so errors are still possible. Artificial intelligence (AI) may provide a better way forward.

By Emily Newton

The Problem With Conventional Calibration

Just as sterility monitoring is only as reliable as its sensors are accurate, calibration is only helpful when it is both comprehensive and precise. That leaves considerable room for human error.

Calibration mistakes and other human errors are a common cause of equipment downtime in health care and pharmaceuticals. It is easy not to calibrate a sensor along its entire range or to adjust a machine incorrectly according to test results. Maintaining utmost care takes a lot of time and focus — two things which are typically not humans’ strong suit.

Manual testing and adjustment can also be slow, which creates two issues. First, it means extended machine downtime, leading to lost productivity. Second, it means the employees performing this work may get tired, overloaded and distracted, raising the risk of human error all the more.

In light of these shortcomings, it should be no surprise that calibration drift may be more common than companies realize. Thankfully, there is another way.

Where AI Comes In

Like many pharmaceutical processes, calibration drift tests can benefit heavily from automation. AI-enabled calibration automation is becoming increasingly commonplace, and it is unlocking new standards of sterility assurance in several areas.

Automated Calibration Drift Tests

At its most simplistic, AI can automate the same kinds of sensor tests a human would normally perform. This has two main advantages — accuracy and efficiency.

Humans are infamously prone to mistakes when taking on repetitive, data-heavy work. Pharma entities lose millions of dollars annually because of these errors, but the workflows people struggle with are typically where AI is most reliable. Consequently, a sensor array that detects and corrects its own calibration drift will make more accurate adjustments than a manual process.

Automated testing and tweaking also mean lab staff do not need to take time out of their busy days to perform such work. The equipment will correct sensor accuracy issues as soon as they are measurable, so labs avoid scheduling complications, too.

Adaptive Calibration

AI-driven sensor calibration can also adapt over time. As machine learning models get new information, they can adjust their approaches to account for larger trends. That way, auto-calibrating systems can manage things like wear, temperature fluctuations and more, which may cause conventional strategies’ dependability to vary over time.

These ongoing improvements are especially valuable when dealing with equipment with broad factory calibration settings. Expert calibration can make tools more accurate, turning cheaper machinery into top-of-the-line assets. In addition to preventing sterility reading errors, this can save money on lab equipment.

Predicting Calibration Drift

Some AI models can even predict calibration drift before it happens. Predictive analytics models will learn how frequently sensors need calibration and what events lead to it as they monitor the system. They can then recognize when adjustments will be necessary in the future for more proactive steps.

It is the same underlying concept as predictive maintenance, which can reduce downtime by 15% and has become popular among manufacturers. Instead of predicting breakdowns, though, the model detects the risk of calibration drift before it occurs so it can recalibrate sensors early and prevent errors entirely.

Eliminating calibration errors means sterility monitoring tools remain as accurate as possible throughout their useful service lives. That presents massive savings potential and makes regulatory compliance much easier.

Remaining Obstacles With AI Calibration

AI-driven calibration is too promising to ignore. At the same time, it is easy to get stuck in the same trap with AI as the one leading to undetected calibration drift in the first place. No technology is perfect, so over-relying on it is a sure path toward significant issues.

Most notably, AI needs a lot of high-quality data to be reliable. This data demand can result in lengthy, expensive model training processes, which may weaken some of the calibration’s cost-saving impacts. Even the most reliable machine learning models can still hallucinate, too, so experts must verify the work periodically to ensure everything stays on track.

Some sterility sensor arrays are also not the most computationally complex systems. While that is good news for affordability and ease of use, it also means not all equipment has the hardware to support an advanced AI model. Consequently, implementing self-calibrating models can entail some costly upgrades. The resulting savings should compensate for the investment over time, but the initial expense remains a barrier for some labs.

AI Calibration Can Unlock New Standards of Sterility Assurance

While it may not be perfect, AI calibration shows a lot of promise. Labs that invest in it now and account for its shortcomings could make their sterility assurance processes more efficient, accurate and reliable than ever. AI is not a panacea, but it is a big step in the right direction.

Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Means, Ranges and Replicates: Improving Microbial Plate Counting

A microbial colony is a visible cluster of microorganisms growing on the surface of or within a solid medium. This may be from a single cell or an amalgam of the same organism of more than one cell or a mix of different organisms. Bioburden levels are commonly measured when conventional methods are deployed in terms of colony-forming units (CFUs). These units provide an estimation of the number of viable bacteria or fungal cells found on a sample, expressed against a unit of measurement, such as per millilitre or per milligram.

When counting CFUs on solid microbiological culture media (agar) there are some aspects of ‘counting’ that need to be considered. These are:

a) Rounding and averaging

b) Significant figures

c) Countable range

d) Statistical error from low counts

This article looks at each of these aspects of the microbial plate count.

Sandle, T. (2025) Means, Ranges and Replicates: Improving Microbial Plate Counting, European Journal of Parenteral and Pharmaceutical Sciences, 30 (1): https://www.ejpps.online/post/means-ranges-and-replicates-improving-microbial-plate-counting 
 

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

From Flat to Functional: Recreating Human Microbial Environments with 3D Bioprinting

 

Image: Bioprinting of 3D Convoluted Renal Proximal Tubules on Perfusable Chips.Source: Homan K, Kolesky D, Skylar-Scott M, Herrmann J, Obuobi H, Moisan A, Lewis J (2016). "Bioprinting of 3D Convoluted Renal Proximal Tubules on Perfusable Chips". Scientific Reports. DOI:10.1038/srep34845

Not all microorganisms are harmful. In fact, our body naturally hosts tiny organisms like bacteria, viruses, and fungi that play essential roles in maintaining our health. Together, these helpful microbes make up what is known as the human microbiome. These beneficial bacteria and fungi aid in digestion, fight off harmful germs, and strengthen our immune system.

By Hannah Vargees 

Interestingly, these microbes don’t just interact with each other—they also interact closely with host tissues, immune cells, and environmental factors like pH levels, oxygen gradients, and nutrient availability within our body. Understanding these complex interactions is vital, especially when studying diseases or developing targeted therapies.

To study these interactions, scientists have traditionally relied on 2D cell cultures and animal models. But each of these approaches has its limitations.

First, let’s understand what 2D cell culture is. It involves growing human or animal cells on flat surfaces like plastic or glass dishes. These cells absorb nutrients from the surrounding media and spread out across the flat surface. While it’s a widely used and cost-effective technique, it doesn’t truly replicate how cells grow and behave in the human body. Flat growth alters cell behavior and signaling pathways, making it hard to recreate realistic tissue environments. Additionally, 2D cultures can’t support key features like biofilm formation or mucosal layering, both of which are essential for mimicking human microbial environments.

Next, we have animal models, which are commonly used to study diseases and drug responses. However, they come with their own challenges. There are species-level differences that are difficult to account for, and the immune responses in animals often differ from those in humans. This makes it challenging to translate findings directly into clinical outcomes, limiting their usefulness in drug development and microbiome studies.

This is where 3D bioprinting offers a promising solution. It allows scientists to precisely place cells in spatial arrangements that replicate tissue-like structures, enabling a more accurate and dynamic model of the human body. To create these structures, researchers use bioinks made from hydrogels like GelMA or alginate, which help simulate the natural tissue environment more effectively.

Hydrogels are particularly useful because they closely mimic the extracellular matrix (ECM) found in real tissues. They support cell growth, differentiation, and allow for the controlled diffusion of nutrients and oxygen. Moreover, they’re biocompatible and tunable, meaning they can be adjusted to match the mechanical and biochemical properties of specific tissues or organs.

In summary, while 2D cultures and animal models have laid the groundwork, 3D bioprinting is pushing the boundaries of how we study the microbiome and human health, offering more accurate, ethical, and customizable tools for modern research.

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

How Vaccines Are Shaping the Global Public Health Landscape

Vaccines have long stood as one of the most powerful tools in the arsenal of public health. From eradicating smallpox to curbing the spread of polio and mitigating the devastating effects of COVID-19, immunizations continue to transform the health trajectories of entire populations. As the 21st century unfolds, vaccines are not only protecting billions from infectious diseases but are also reshaping global healthcare systems, economies, and policy frameworks. This article explores how vaccines are redefining public health, addressing challenges, and pointing toward a more resilient and equitable future.

The vaccines industry was valued at USD 119.1 billion in 2022 and is projected to grow at a compound annual growth rate (CAGR) of 4.2% from 2023 to 2031. By the end of 2031, the market is expected to reach USD 99.3 billion, driven by continuous innovations, increasing demand for immunization, and advancements in vaccine technology.

A Historical Turning Point

The history of vaccination dates back to the late 18th century with Edward Jenner’s smallpox vaccine. This moment marked the beginning of modern immunology and showcased the power of pre-emptive medicine. By the late 20th century, vaccines had led to the eradication of smallpox globally in 1980—a monumental achievement made possible by a coordinated international effort. The global incidence of diseases like diphtheria, measles, and tetanus dropped drastically due to widespread immunization campaigns.

The early success of vaccines laid the foundation for global public health strategies, shifting the focus from reactive treatment to proactive prevention. Over time, this has resulted in millions of lives saved, increased life expectancy, and improved quality of life across all continents.

Modern Vaccination: Expanding the Scope

In recent decades, the scope of vaccines has expanded significantly. No longer limited to childhood diseases, vaccines now target a broad spectrum of illnesses affecting people of all ages. For instance:

•    HPV vaccines help prevent cervical and other types of cancers.
•    Influenza vaccines are updated annually to combat ever-evolving viral strains.
•    COVID-19 vaccines rapidly developed using novel mRNA technology represented a leap forward in both science and logistics.

The development and deployment of new vaccines have also helped address emerging threats, such as Ebola and Zika. Importantly, the infrastructure built for COVID-19 vaccination campaigns—cold-chain logistics, data management, and public communication—now serves as a template for future public health initiatives.

Public Health Impact: Numbers That Matter

The benefits of vaccination are quantifiable and wide-ranging. According to the World Health Organization (WHO), vaccines currently prevent more than 5 million deaths annually from diseases such as measles, diphtheria, tetanus, pertussis, and influenza. A study published in The Lancet in 2021 estimated that between 2000 and 2019, vaccination efforts against ten major diseases prevented 37 million deaths globally.

Beyond mortality, vaccines reduce the burden on healthcare systems. They minimize hospital admissions, reduce the need for antibiotics (thereby combating antimicrobial resistance), and help avoid the long-term complications associated with many infectious diseases.

Economic benefits are also substantial. Every $1 spent on immunization is estimated to yield up to $44 in economic returns when considering productivity gains, healthcare savings, and avoided disease outbreaks.

Driving Equity and Access

Vaccination programs are crucial for promoting health equity. They are often the first line of healthcare in underserved communities and are integrated into national and global development agendas. Initiatives like Gavi, the Vaccine Alliance, and the COVAX facility have played pivotal roles in ensuring vaccine access in low- and middle-income countries.
Gavi, for instance, has helped immunize over 1 billion children since 2000, preventing over 17 million deaths. By subsidizing vaccine costs and supporting national health systems, such partnerships are bridging the gap between high-income and resource-poor countries.
Furthermore, immunization campaigns often reach remote and vulnerable populations, improving access to other essential health services such as nutritional support, maternal care, and disease screening.

Challenges on the Path Forward

Despite these advances, several challenges threaten to undermine global vaccination efforts:

1. Vaccine Hesitancy
One of the most pressing issues is vaccine hesitancy, fueled by misinformation, mistrust in governments, and social media conspiracies. The WHO listed vaccine hesitancy among the top 10 global health threats even before the COVID-19 pandemic. Countering this requires multifaceted approaches, including public education, transparent communication, and engaging trusted community leaders.

2. Supply Chain and Infrastructure
In many parts of the world, delivering vaccines to every individual is a logistical challenge. Poor infrastructure, lack of cold-chain storage, and conflict zones hinder access. Investments in transportation, refrigeration technology, and digital tracking systems are critical to ensure equitable distribution.

3. Emerging Diseases
New pathogens continue to emerge due to climate change, urbanization, and globalization. Rapid vaccine development, as demonstrated during COVID-19, must become the norm rather than the exception. This demands global cooperation in funding, research, and regulatory harmonization.

4. Global Disparities
There remains a stark contrast in vaccination rates between countries. While high-income countries boast over 90% coverage for most vaccines, many low-income nations struggle to surpass 60%. These gaps leave large populations vulnerable and increase the risk of disease resurgence.

Innovation and the Future of Vaccines

Science is continuously advancing the potential of vaccines. A few promising developments include:

•    mRNA Technology: Beyond COVID-19, mRNA platforms are being explored for HIV, tuberculosis, and cancer vaccines. Their adaptability and faster production cycles could revolutionize global response to new diseases.

•    Needle-free Vaccines: Innovations such as microneedle patches or oral vaccines aim to make immunization more accessible and acceptable, especially for children and those with needle anxiety.

•    Personalized Vaccines: For diseases like cancer, researchers are working on individualized vaccines based on a patient’s genetic profile to target specific tumor antigens.

•    Universal Vaccines: Projects like a universal flu vaccine aim to protect against all strains, reducing the need for annual updates and increasing reliability.

Vaccine Diplomacy and Global Cooperation

Vaccines have also become instruments of soft power and diplomacy. Countries that produce and distribute vaccines often gain geopolitical influence, building alliances and promoting international goodwill. However, the pandemic also exposed the darker side of “vaccine nationalism,” where wealthier nations hoarded doses, delaying access for poorer countries.

To build a more just system, the global community must embrace collaborative frameworks that prioritize collective security over individual gain. Mechanisms such as the Pandemic Treaty being discussed by WHO aim to ensure more equitable access and preparedness for future health emergencies.

Gather more insights about the market drivers, restrains and growth of the Vaccines Industry

CGMP Requirements For Automated Facility Monitoring Systems

 

Monitoring systems (image by Tim Sandle)

In pharmaceuticals and healthcare, “facility” refers to the operational space, such as a cleanroom. The critical controls that maintain the facility are delivered through key utilities like air handling systems. To assess facility control, most organizations use facility monitoring systems (FMSs) to monitor the manufacturing workspaces continuously. Such systems are designed to be always on when the facility is in the operational state, ensuring compliance with important parameters across identified ranges. An important element for microbiological control is particle counting, which verifies the class of the cleanroom and indicates how well control is being maintained. Interconnected devices provide continuous monitoring of facilities, including aseptic and controlled environments. Other environmental data is also of importance for the contamination control strategy, including temperature, humidity, air velocity, and pressure. The design of these automated environmental monitoring systems should be based on quality risk management principles.

Sandle, T. (2023) CGMP Requirements For Automated Facility Monitoring Systems, Outsourced Pharma, August 2023: https://www.outsourcedpharma.com/doc/cgmp-requirements-for-automated-facility-monitoring-systems-0001

Also in:

BioProcess Online: https://www.bioprocessonline.com/doc/cgmp-requirements-for-automated-facility-monitoring-systems-0001
Pharmaceutical Online: https://www.pharmaceuticalonline.com/doc/cgmp-requirements-for-automated-facility-monitoring-systems-0001
Cell and Gene: https://www.cellandgene.com/doc/cgmp-requirements-for-automated-facility-monitoring-systems-0001
Biosimilar Development: https://www.biosimilardevelopment.com/doc/cgmp-requirements-for-automated-facility-monitoring-systems-0001
 

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

Addressing human factors in decontamination

Ensuring that surgical processing departments are well-run is of great importance, as these departments are responsible for decontaminating reusable surgical equipment and for delivering it, as required, to operating theatres. Decontamination involves several  processes, occurring within dedicated facilities, including cleaning, disinfection and sterilisation, which ensures reusable surgical instruments are safe for further use on patients.

The operation requires maintaining a well-ordered facility, ensuring it is clean and decontamination practices can be consistently reproduced. While most units have well-written procedures, human errors will happen and these can sometimes lead, in the most serious cases, to the transference of contamination and patient infection (healthcare-associated infections). While human failure is normal and predictable, it can be identified and managed. Hence, errors can be reduced by reviewing how surgical processing departments are managed and how personnel operate, in particular, by reducing the level of variability. An approach that can deliver success in this area is the ‘human factors method’.

This article looks at three areas where human factors approaches can assist with improving performance through lowering variability and, hence, reducing contamination rates. These are: Development of procedures; Training; Space and ergonomics. Prior to this, the article introduces the subject of human factors and looks at sources of variability within surgical processing departments.

Sandle, T. (2023) Addressing human factors in decontamination, Clinical Services Journal, 22 (7): 39-43
 

To read, see: Human Factors

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

Glove disinfection and aseptic technique: Creating a schema for the cleanroom and laboratory

 

There are different elements that contribute to good aseptic technique within the cleanroom and the laboratory. One such element is the donning of gloves, handling items appropriately, and keeping gloves regularly disinfected. Glove disinfection is an essential step for bacteriological control, although how successful control is maintained is dependent upon the type of disinfectant (these are generally alcohols for gloved hands), frequency of application, volume of disinfectant, application technique and the contact time. Other variables include purchasing gloves of a suitable material and design, and appropriate training. Aa an added control with more critical areas, the gloves are pre sterilised before donning (often purchased sterile by radiation or ethylene oxide).

As with other types of disinfection, the aim is not ‘sterilisation’ but to bring any bacterial density present on the gloves down to a level that is as low as possible (what is sometimes referred to as the "irreducible minimum"). Assessment, when required, is commonly through the use of agar contact plates onto the fingertips of each gloved hand (four fingers and the thumb) to create the ‘finger plate’ or ‘finger dab’. To avoid false negatives, the agar needs to be formulated with an appropriate disinfectant neutraliser.  

For cleanroom and laboratory managers seeking to maximise the maintenance of asepsis, glove control is an important element. This should take the form of a good practice schema and for this to be transitioned into a training module, supported by regular prompts in practice.  

In terms of what such a schema should look like, this article appraises the research that underpins an appropriate glove ‘sanitisation’ schema. This includes the central concerns of when and how effective glove disinfection is to be achieved. The key findings are that a 30 second disinfection time is suitable for both cleanroom and laboratory operations, provided a suitable technique is deployed and an alcohol-based disinfectant used. However, controls need to be in place to avoid the over disinfection of gloves since repeated applications increase the likelihood of microperforations occurring and thereby effective glove disinfection needs to be supported by a regular glove change procedure.  

Sandle, T. Glove disinfection and aseptic technique: Creating a schema for the cleanroom and laboratory, European Journal of Parenteral and Pharmaceutical Sciences, 28 (2): https://doi.org/10.37521/ejpps.28201
 

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

Key considerations for the selection of pharmaceutical equipment cleaning chemicals

Cleaning validation verifies the effectiveness of cleaning processes within pharmaceutical and healthcare facilities. It should be directed to situations or process steps where contamination or the carryover of materials pose the greatest risk to product quality (1), as evaluated to appropriate limits (2). To ensure cleaning process robustness, care must be taken in the selection of cleaning chemicals. This article looks at the choices available and some of the important selection factors for cleaning chemicals.

To determine the most appropriate chemicals, an understanding of the products is needed, especially with the selection of the most appropriate in-process material for the cleaning validation (3). This choice should be based on factors like solubility, difficulty of cleaning, the different types of equipment to be cleaned and the calculation of residue limits based on potency, toxicity, and stability.

Sandle, T.: Key considerations for the selection of pharmaceutical equipment cleaning chemicals, RSSL Insights, April 2023: https://www.rssl.com/insights/life-science-pharmaceuticals/key-considerations-for-the-selection-of-pharmaceutical-equipment-cleaning-chemicals/
 
Posted by Dr. Tim Sandle, Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)

Small Steps to Giant Leaps: Advancing Data Integrity in Sterility Testing

Webinar

With Sterility Testing serving as the final critical data point for product release to the public, the Pharmaceutical Industry is continually looking to methods which will increase efficiencies and reduce errors.

What if there was a software that could work with your existing Steritest^® Symbio pump and also allow you to digitally capture every step of the Sterility test? 

You may have already about the M-Trace^® 21 CFR Part 11 compliant solution, giving step-by-step handling instructions, while collecting all relevant data in realtime. The system has launched its second version, which is now Microsoft Windows compatible, providing easier integration in your company IT infrastructure.

Agenda:

• M-Trace^® solution existing and new features that enable seamless integration with your Steritest^® Symbio pump and with your current IT environment
• Importance of capturing every action during Sterility Testing to improve operational efficiency and reduce errors
• Practical examples of how digitalization can transform your facility's testing procedures and support compliance with Standard Operating Procedures (SOPs)
• Live Q&A

Speakers:

• Michel van Musschenbroek: Regional Application & Commercial Tactics Manager, North America, Merck KGaA
• Nicolas Lelièvre: Regional Application & Commercial Tactics Manager, Western Europe, Merck KGaA

Language:

• English, but live translation in Japanese and Spanish (subtitles)

Time and date

May 13 at 10:00am CEST (Paris) / 4:00pm SGT (Singapore) / 5:00pm JST (Tokyo)     

Link to register: https://event.on24.com/wcc/r/4903610/5BDE8D3C78E8CDB11007DF9A05049616?partnerref=PMRWeb

 

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

New store for microbiology themed gifts: BabblingBacteria

 

BabblingBacteria is a new shop selling a range of microbiology themed gifts, uniquely designed by Tim Sandle.

T-shirts, color chnaging mugs, cool posters, light catching decorations and even a special irradiation fragrenced candle!

Please visit here: Babbling Bacteria.

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

Best practices for pharmaceutical microbial data investigations

Assessing microbiological data and undertaking investigations into the origins of contamination, establishing root causes, and setting appropriate preventative actions constitutes a core part of the contamination control strategy. Despite the importance of this process, regulatory findings frequently cite poor quality microbial investigations.

This article looks at the main steps involved for conducting investigations and provides some best practice advice for the company microbiologist. The goals here are to help to structure investigations that are:

Simple:    Easy to execute and to understand,
Effective:    Producing the correct result.

The advice is presented as a series of phases. While the phases represent activity blocks, they should not necessarily be thought of as discrete entities for they can run concurrently or may overlap. This is especially useful in order to complete a detailed and thorough investigation within a reasonable timeframe (as with other investigations undertaken within pharmaceuticals, a target of 30 days is often applied).
 

See:  https://www.americanpharmaceuticalreview.com/Featured-Articles/596293-Assessing-Microbial-Contamination-Best-Practices-for-Pharmaceutical-Microbial-Data-Investigations/?cid=26759

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

Cleaning Up in BioPharma

As the therapeutic landscape grows more complex, so too must the analytical techniques for cleaning validation to ensure the utmost cleanliness is achieved.

Within the bio/pharma industry, there is a certain expectation for companies to maintain required levels of cleanliness within their facilities to ensure products that are manufactured are at minimal risk of contamination. All cleaning processes must also be validated for effectiveness and reproducibility.

As drug products become more complex and sensitive to potential contaminants, there is an increasing demand for cleaning validation throughout industry. According to market research, the cleaning validation market is forecasted to grow by a compound annual growth rate of 5.7% between 2021 and 2027.

See: https://www.biopharminternational.com/view/cleaning-up-in-bio-pharma
 

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

Four Ways to Minimize Operational Risk in Cleanrooms

What would it cost your business if your cleanroom was down for a day? A week? A month? The financial impact could be staggering, with potential revenue losses reaching into the millions. On average, there are over 500,000 detectable earthquakes each year. Of those, at least one major earthquake—those with a magnitude of 7.0 or higher— takes place each month, bringing the risk of severe damage and even casualties.

For the pharmaceutical industry, cleanroom downtime can cost between $10,000 and $50,000 per day. For semiconductor manufacturing, that cost rises significantly, ranging from $100,000 to $1 million per day. With their potential to disrupt structural integrity, airflow, and equipment, earthquakes can quickly compromise the very essence of what makes a cleanroom effective: cleanliness and contamination control.

Seismic-rated cleanrooms are becoming increasingly important, particularly in earthquake-prone regions such as California, Oregon, and Washington. In this article, we highlight the six considerations cleanroom professionals need to keep in mind when building a seismic-rated cleanroom and why these precautions are vital for operational safety, regulatory compliance, and avoiding cleanroom downtime.

How Earthquakes Impact Cleanrooms

In its simplest form, a cleanroom is designed to prevent particle contamination and create a controlled environment, factoring in temperature regulation, air filtration, and air flow. Seismic events can cause structural damage to cleanrooms, including cracks in the walls, damaging internal partitions, and even result in collapsed ceilings. When this occurs, the delicate, controlled environment can quickly become contaminated, jeopardizing both operations and the safety of those working within it.


“During an earthquake, the shifting foundation of the building that the cleanroom sits on and the goal of maintaining the precise environment is the biggest challenge,” said Mark Zabala, senior sales manager at SERVICOR™ by Nortek Air Solutions. “Cleanrooms in areas with earthquake risk need to be designed to not only survive the event, but also to maintain their cleanroom classification level in order to remain operable.”


Seismic standards are put in place to ensure that buildings and structures can withstand the forces of an earthquake. During an earthquake, not only is the structural integrity of the building at risk, but so is the safety of occupants and the delicate process taking place in the cleanroom.


California sits in a seismic zone 4 and experiences two to three major earthquakes each year. “In California alone, our modular cleanrooms, SERVICOR™, have experienced at least 90 earthquakes since 1983,” explained Zabala. “When we design a cleanroom for seismic rating, we engineer the cleanroom to exceed seismic zone 4 requirements, not only ensuring that operations continue after a seismic event, but eliminating the concern that if relocated to a different location, the cleanroom would need to be re-engineered to meet stricter seismic zone requirements.”


From the destruction of expensive equipment to contamination risks, or even the injury of personnel, a poorly designed cleanroom could expose an organization to catastrophic losses. The seismic rating of a cleanroom ensures that both the building and its contents are secure in case of an earthquake.


Each day of downtime means halted production, missed deadlines, and dissatisfied customers. In an industry where precision and reliability are paramount, even a minor disruption can have major financial repercussions.


Designing to Minimize Risk and Revenue Loss

Taking into account the frequency of earthquakes and where the cleanroom will operate, there are four factors to keep in mind:


1. Meeting versus Exceeding Seismic Ratings

Before designing a cleanroom, it’s crucial to understand the seismic requirements specific to its future location. In the U.S., there are four seismic zones based on the level of seismic activity, with zone 4 attributed to the highest risk zone.


Pacific coast states California, Oregon, and Washington are in high seismic zones, requiring their cleanroom structures to be built to withstand earthquakes of considerable size. Specifically, California requires all cleanrooms to meet seismic zone 4 standards. With the likelihood of a magnitude 8 or larger earthquake hitting California in the next 30 years rising from 4.7% to 7.0%, designing for seismic activity continues to be more important than ever.


With the flexibility in modular cleanrooms to be adaptable and moveable for future use, cleanroom owners should consider the lifespan of their cleanroom needs, not just where the cleanroom will sit today. “We designed SERVICOR™ to exceed seismic zone 4 requirements, eliminating the need for retrofitting the cleanroom if it is moved to a higher seismic zone and giving operators the peace of mind, no matter where the cleanroom sits,” said Zabala.


2. Designing for Load Distribution

Weight load distribution is critical in seismic-rated cleanrooms. Each piece of equipment should be appropriately anchored to ensure that it does not shift, tip, or fall during seismic activity. “When we design a cleanroom with steel ceilings, like SERVICOR™ Modular Cleanrooms, we eliminate the need for hangers, which allows us to design a self-supporting cleanroom and ultimately achieve a seismic rating,” said Zabala. The welded ceiling grid modules cradle the often heavy ceiling components including lights, ceiling tiles, and fan filter units. These features create the sturdy structure, while minimizing additional load and strain to the existing structure.


A self-supported cleanroom system does not rely on support from the building’s structure and is designed with floor anchors to ensure stability, minimizing the risk of a cleanroom being damaged or collapsing during an earthquake. This approach prevents unnecessary load on the building’s existing infrastructure and reduces the potential for cascading failures.


3. Working with a Structural Engineer

One of the key steps when building a seismic-rated cleanroom is collaborating with licensed structural engineers to perform thorough calculations and provide certification. Structural engineers are critical in evaluating the seismic impact on cleanroom systems and ensuring that the design meets local codes and regulations.


Engineers will conduct detailed analyses to ensure that the cleanroom’s materials and systems are designed to absorb and distribute seismic forces evenly, reducing the risk of structural failure. “Once the drawing process is complete, plans are sent to a structural engineer to confirm compliance,” explained Zabala. “If any modifications are required, they’ll be submitted for customer approval and proceed with manufacturing.”


4. Maintaining the Cleanroom

Maintenance and inspections are standard requirements to ensure that a cleanroom is operating at the required class level/ISO level. Cleanrooms are dynamic environments with equipment that needs continual monitoring, in fact the lack of appropriate monitoring and documentation is one of the most common pitfalls cleanroom operators have. With modular cleanrooms providing ultimate flexibility, any future upgrades or reconfigurations need to adhere to seismic rating standards.

The Risk of Not Being Prepared

Not only is there significant revenue loss when a cleanroom is down, but there are the significant costs of replacing damaged equipment. In fact, the cost of non-structural elements in a cleanroom accounts for nearly 80-90% of the total cleanroom cost, including the costs of repairs, replacing damaged equipment, and the lost productivity.

Equipment Replacement: Cleanrooms often house sensitive equipment, including microscopes, manufacturing tools, and other specialized equipment. All would need to be tested to ensure it is properly functioning and potentially replaced.


Contamination Control: If a contamination occurred during an earthquake, not only would the products within it be compromised and lead to quality issues, but the cleanroom itself would need extensive cleaning and decontamination to restore to proper usability.


Managing Insurance Premiums: Buildings with seismic ratings often have lower insurance premiums due to the reduction in risk, which can range from 10-20%. On the flip side, premiums may increase after an earthquake if the cleanroom is not rated for the correct seismic zone.

“A seismic-rated cleanroom isn’t just about surviving an earthquake,” concludes Zabala. “It’s ensuring that operations can continue as smoothly as possible. With the right partner, materials, systems, and planning, you can create a space that is as resilient as it is clean.”


With an increase in cleanroom demand, designing for structural resilience and maintaining the integrity of cleanroom systems, even during a power outage, are important to minimizing contamination within a cleanroom. With experienced cleanroom partners and proper planning, cleanrooms can withstand seismic events and maintain required cleanliness levels.


About Mark Zabala

With 19 years of experience in the cleanroom industry, Mark Zabala’s comprehensive skill-set spans field installations, site coordination, cleanroom design, and engineering. Mark has been involved with IEST as a voting/contributing member in several working groups, as well as an active member of ISPE, ASHRAE, and SEMI. His extensive background enables him to gather critical insights in his role as senior sales manager at Nortek Air Solutions CleanSpace that lead to the successful implementation of cleanroom systems for customers and partners alike.


About Nortek Air Solutions

With world-class brands like CleanPak®, Huntair®, SERVICOR®, Temtrol®, Governair® and Mammoth® Nortek Air Solutions produces innovative, safe cleanroom solutions that meet and exceed strict contaminant and particulate-free environment standards so that customers can continue creating products that make the world safer, healthier, and more productive. Nortek Air Solutions has engineered over 20 million square feet of cleanroom systems that exceed strict contaminant and particulate-free regulations to keep the world’s most innovative spaces running. Learn more about NortekAir.com. 

Pharmaceutical Microbiology Resources (http://www.pharmamicroresources.com/)