Meg ProvenzanoProduct Manager, Bio-Detection
Briana NuñezMicrobiology Technical Specialist
Veolia Water Technologies & Solutions, Sievers Instruments
Time matters. Everyone in pharmaceutical manufacturing is busy, making it imperative to find better monitoring tools. In particular, bioburden monitoring and bacterial endotoxin testing (BET) are areas in need of improvement. These contaminants are high risk in any pharmaceutical manufacturing site and should be monitored as quickly and easily as possible. However, these tests are traditionally time-consuming and require significant hands-on time.
Whether it’s performing tests, managing investigations, or signing off on paperwork, manufacturers need to be able to provide bioburden and endotoxin data quickly to manage the quality of products, raw materials, and in-process samples - all while keeping the process under control.
Now, with advances in instrumentation, bioburden and endotoxin testing are significantly faster and easier, improving the effectiveness of a monitoring program in alignment with EU GMP Annex 1. The revised Annex 1 urges sterile manufacturers to consider implementation of innovative technologies such as Rapid Microbiological Methods (RMMs) to improve the effectiveness of microbial monitoring and quality of final product.
Along with the benefit of enhanced monitoring, implementation of new tools such as the Sievers Soleil Rapid Bioburden Analyzer and Eclipse BET Platform can provide efficiency gains from data integrity, ease of use, and fewer human errors to impact the final product.
How can microbial testing be faster and easier?
With the use of rapid micro methods and simplified testing, you can improve control and have a better understanding of your entire process. Efficiency is achieved using innovative technologies that make testing faster, also requiring less hands-on time and fewer pipetting steps. As described in recent revisions to Annex 1 which went into effect in August 2023, there are benefits of implementing rapid methods to improve contamination control strategies. Faster and more efficient methods for bioburden and endotoxin testing will increase the protection of products and environments, and areas such as personnel, equipment, facilities and materials all offer opportunities to introduce tools for easier process monitoring.
Rapid bioburden methods
Traditional methods for microbial testing take days. These tests not only delay the production process, but lack the ability to provide real-time information to drive ongoing decision-making. The Sievers Soleil Rapid Bioburden Analyzer provides results that correlate to plate counts in less than 45 minutes. This is achieved using unique viability stains in conjunction with ultra-sensitive optics to provide users with results that correlate to traditional methods.
Advantages include:
- Make timely data-driven decisions about the manufacturing process to reduce risk, increase cost savings, and enable greater confidence when releasing products
- Perform testing in a laboratory or at-line throughout manufacturing to monitor contamination control processes within water systems, cleaning validation, environmental monitoring, raw materials, and drug substances
- Easily perform testing with only three pipetting steps
- Remove the bioburden testing bottleneck in product release
More efficient endotoxin testing
Traditional endotoxin assays are time-consuming, error-prone, and difficult to perform. They also rely heavily on resources. Historical options for BET include traditional 96-well microplate assays that are manual and not ergonomically friendly. Automation with robots can be prone to errors using multiple softwares to control the instruments and still require many liquid handling steps. In recent years, recombinant technologies have gained popularity, however they are not considered compendial globally. They are also still prone to user error, with manual pipetting steps. In addition, these various methods leave room for improvement in terms of speed, footprint, hands-on time, complexity of validation, sustainability, and compliance.
The Sievers Eclipse microfluidic endotoxin testing system enables users to set up fully compliant assays in less than ten minutes with a 90% reduction in Limulus amoebocyte lysate (LAL) reagent and only 55μL of sample. With this technology, BET assays are simple, easy and compedial and can be performed with your choice of commercially available kinetic chromogenic reagent. Assays are remarkably easier, as you don’t need to make your own standard curve - it’s already preloaded on the microplate along with positive product controls (PPCs).
Advantages include:
- Faster turnaround times, minimal training, and improved sustainability
- Less analyst hands on time and less chance of manual errors due to 5-10 minute setup time with 89% fewer pipetting steps than 96-well plate
- Easily train production technicians and analysts on simpler, faster endotoxin testing procedures
- Intuitive, highly customizable software with full 21 CFR Part 11 compliance capabilities
- Reduced cold room storage - store microplates at room temperature and reduce the number of reagents needed to store in 2-8°C
- Increased sustainability - reduce LAL usage (1mL LAL per plate)
What can be gained from greater manufacturing agility?
A combination of rapid micro methods and microfluidic technology can lean out the bioburden and endotoxin testing processes within your facility. This allows you to get results quickly and make faster, actionable decisions to mitigate risks and increase efficiencies throughout manufacturing. The goal is to increase your manufacturing agility and reduce delays in production.
When designing and implementing a contamination control strategy (CCS), it all starts with a culture of quality. A robust CCS can help you decrease risks for out-of-specification (OOS) investigations and reduce cost and unnecessary use of resources. A focus on quality keeps process control at the forefront to ensure product standards are met. This means deviations are quickly identified and addressed. New and innovative technologies allow for this proactive approach by making monitoring of processes and products easier and more reliable. These technologies also mitigate risks such as time to results, risk to the business, and risk to the process.
Conductivity, total organic carbon, endotoxin and bioburden are four parameters that are critical to test in pharmaceutical water systems. To improve process control and understanding, and to achieve compliance, manufacturers are encouraged to use technologies that help track and trend data, make real-time decisions, and optimize uptime with fewer OOS investigations. Manufacturers of sterile products are subject to special requirements in order to minimize risks of microbial, particulate, and endotoxin or pyrogen contamination. The following areas should be considered: personnel, facilities, utilities, equipment, processes, and materials.
Process analytical technologies (PAT) are used as part of methodology to design, analyze, and control the manufacturing process. The ultimate goal of PAT is to ensure the quality and safety of products and processes, with benefits including improvements in product quality, shorter manufacturing times, and faster release of products.
Simplified technologies to make timely, data-driven decisions
Technology that is easier to use is a time saver, and this can be amplified with easier validations and purpose-built software. Simplification of consumables, reagents, and other accessories will also lead to efficiency gains throughout the manufacturing process. For bioburden testing, reducing time to results from days to less than an hour offers significant agility to make important decisions and maximize efficiency and quality. In particular, correlation to plate counts is critical to have the confidence you need to make these decisions. For endotoxin testing, setting up assays in less than ten minutes using a simple platform enables analysts to eliminate the majority of hands-on time, thus reducing errors and retests. Efficiency gains are coupled with improvements in sustainability using 90% less lysate and simplifying reagent use and storage.
Today’s pharmaceutical manufacturing environment requires agility, efficiency, flexibility, and quality. To meet these needs, innovative instrumentation and PAT can be implemented to improve process control and increase speed. With faster microbial detection, you can make timely, data-driven decisions and quickly take action to control contamination events and reduce risk.
Publication Detail
This article appeared in American Pharmaceutical Review:
Vol. 26, No. 8
Nov/Dec 2023
Pages: 62-63
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