Briana Nunez, Meg Provenzano, Hayden Skalski, and Kaitlyn Vap- Veolia Water Technologies & Solutions, Sievers Instruments
Revision of Annex 1 reflects new insights and expectations in the changing pharmaceutical landscape related to the manufacture of sterile products. It clarifies how manufacturers can take advantage of innovative tools - such as real-time monitoring and rapid methods - to enhance process understanding in order to better identify risks and support patient safety. The Annex was revised to reflect changes in regulatory and manufacturing environments and the need to better manage processes, equipment, facilities and manufacturing activities in accordance with Quality Risk Management (QRM) principles. The new guideline takes into account advances in technologies and covers cleanroom, equipment and utility design as well the deployment of new rapid microbiological methods (RMMs).
While the concept of QRM is not new in the pharmaceutical industry, Annex 1 outlines the proactive application of QRM to the manufacture of sterile products to ensure that microbial, particulate and endotoxin/pyrogen contamination is prevented in the final product. Annex 1 provides general guidance for the “design and control of facilities, equipment, systems and procedures used for the manufacture of all sterile products” and should be accompanied by a Contamination Control Strategy (CCS) to assess the effectiveness of all the controls and monitoring measures employed to ensure product quality and safety. According to Annex 1, contamination control “includes a series of interrelated events and measures. These are typically assessed, controlled and monitored individually but their collective effectiveness should be considered together.”
Innovative Technologies for Process Monitoring
To achieve faster, easier process monitoring and contamination control, pharmaceutical manufacturers seek instrumentation and tools that can provide comprehensive information to support critical release tests, including microbiological and chemical monitoring of assessed points to manage risks and allow for proactive decision making. When considering tests for bacterial endotoxin testing (BET), bioburden, total organic carbon (TOC), and conductivity, manufacturers need process analytical technologies (PAT) and monitoring tools that collectively allow for:
- Tracking and trending data
- Real-time decision making
- Optimizing uptime
- Reducing out-of-specification (OOS) investigations
- Maintaining a high standard of quality
Using PAT instruments enables manufacturers to take advantage of innovative technologies to enhance process understanding, improve process control, and mitigate various types of risk. Risks to mitigate include those associated with:
- Time
- Business
- Processes
- Patients
Annex 1 - What are some of the key areas to consider in a contamination control strategy?
According to Annex 1, “development of the CCS requires detailed technical and process knowledge” and “should consider all aspects of contamination control with ongoing and periodic review resulting in updates within the pharmaceutical quality system as appropriate.” The guidance lists various elements to be considered within a CCS. Key areas include:
- Personnel
- Facilities
- Utilities
- Equipment
- Processes
- Materials
The above list is not exhaustive, but it includes key sources of contamination and highlights areas where there is opportunity to introduce technologies for easier process monitoring. In a practical setting, the elements do not operate in isolation, meaning there is often overlap between these elements, and process control serves as the link.
Every CCS starts with a Culture of Quality
When designing and implementing a contamination control strategy, it all starts with a culture of quality. A CCS directly affects patient safety, thus Annex 1 encourages the use of innovative technologies to monitor production processes. This may include PAT instruments for endotoxin testing, bioburden, TOC, and conductivity. With a robust CCS and monitoring tools, companies decrease their risk for out-of-specification (OOS) investigations, thus reducing costs and unnecessary use of resources. A focus on quality keeps process control at the forefront to ensure product standards are met, any deviations are quickly identified and addressed, and that patients receive safe and effective therapeutics.
Rapid bioburden, endotoxin, TOC, and conductivity testing
How can you achieve faster, easier process monitoring? Here are four technologies that enable time-savings, compliance, and risk mitigation:
1. Rapid microbiological methods (RMMs)
Traditional methods for microbiological testing such as bioburden and sterility take days, potentially weeks, to get results. These tests can not only delay production, but they also lack the ability to provide real-time information that drives ongoing decision-making. In order to speed up these tests, companies should consider implementing RMMs that allow for actionable results and can be used for monitoring the entire facility and manufacturing process. Annex 1 states “the adoption of suitable alternative monitoring systems such as rapid methods should be considered by manufacturers in order to expedite the detection of microbiological contamination issues and to reduce the risk to product.”
In particular, companies should consider RMMs where bioburden results can correlate back to plate counts, otherwise the information or data obtained may not be actionable. For example, high throughput flow cytometry for bioburden can provide rapid microbial results compared to traditional methods, and can also correlate back to plate counts. This allows users to make actionable decisions on data that may relate to many elements of the CCS, such as facilities, environmental monitoring (EM), personnel, water systems, equipment, cleaning validation, final product, materials, etc. RMMs can help provide faster turnaround times with regards to in-process materials or packaging, allowing you to release those materials and packaging much sooner into the process.
In contrast, when measuring in auto fluorescence units or another method, the information may not correlate back to plate counts, thus limiting the value of the method and the ability to make actionable decisions. When RMMs are correlated to plate counts, the adoption of these methods within a CCS will be streamlined, and alternative method validation will provide enhanced confidence in the adoption of PAT to minimize time to results and enhance uptime.
2. At-line evaluation of endotoxin
Similar to bioburden, bacterial endotoxin contamination is high risk in any manufacturing site and should be monitored as closely as possible. However, compendial testing for endotoxin contamination has not seen much innovation in 40 years, and traditional methods are prone to errors. Now, with advances in centripetal microfluidic technology, BET assays are set up quickly and easily, providing rapid results compared with traditional methods. Thus, detection of microbial contamination is expedited and risks are reduced across many of the areas discussed in Annex 1 (personnel, facilities, utilities, equipment, cleaning validation, processes, materials, etc.).
Now more than ever, new technologies are widely accepted in lieu of traditional methods, particularly when they offer compendial tests that are faster and easier to perform. This is the case for BET and implementing centripetal microfluidics for more rapid, simple, and compliant testing. Anyone familiar with traditional BET methods is well aware of how time consuming 96-well plate and gel clot assays are. These methods also require highly trained analysts to complete and are prone to mistakes, even for the most qualified technicians.
At-line endotoxin testing is extremely valuable for cleaning validation, process monitoring, or real-time testing, but for these applications, it is imperative to have a testing system that is easy to use and requires minimal training for the analyst. By implementing microfluidics with the Sievers Eclipse BET Platform, compendial assays require less skill from the analyst, less training, and less setup time and time to results. This allows companies to use highly skilled analysts for other activities that they might be able to optimize or where they can provide greater value. By simplifying endotoxin testing with innovative centripetal microfluidic technology, assays can easily be performed as part of the CCS. The Sievers Eclipse provides compendial endotoxin assays that don’t require highly trained microbiologists and require drastically fewer pipetting steps, thus allowing companies to get results faster and easier.
Microfluidic technologies also contribute to sustainability goals. With centripetal microfluidics in the Sievers Eclipse, LAL use is reduced by 90% compared to traditional 96-well plate and gel clot assays. Companies seeking to implement technologies that support their CCS and sustainability goals should consider centripetal microfluidics for faster, easier endotoxin testing that is compendial and conserves resources.
3. Real-time release testing (RTRT) and continuous monitoring for water systems
Annex 1 states that water for injection (WFI) systems “should include continuous monitoring systems such as TOC and conductivity, as these may give a better indication of overall system performance than discrete sampling.” Ultimately, continuous monitoring will provide a better gauge on the level of potential contamination that a water system could be under. Implementing technologies like real-time testing of TOC and conductivity, at-line evaluation of endotoxin with microfluidic technology (see previous section), or bioburden with rapid microbial methods (see previous section) will be key to detect contamination before water enters upstream production processes. These monitoring approaches are ultimately decreasing the time to results and optimizing overall uptime of production.
The Sievers M500 and Real-Time Release Testing validation support from the Sievers team enable pharmaceutical manufacturers to successfully and compliantly implement RTRT into their facilities. With the adoption of any new instrument to a facility comes validation, and for the implementation of RTRT with process analytical technology, process validation is key. There are inherent risks associated with the transition from traditional lab-based testing to online release testing, and those include having a singular instrument monitoring an entire facility, or an entire loop of water. Additional testing would include performing a risk assessment to assess which points of use might be most critical to the process and product. Once identified, a company must then understand how that criticality affects the cleanliness of those points of use. This represents a singular example of a process validation step, and there is more associated with the overall process validation. With validation support from the Sievers Instruments team, companies feel confident about adopting compliant real-time testing or monitoring strategies to enhance their contamination control portfolio.
4. Continuous monitoring for cleaning validation
Cleaning validation samples are frequently tested to ensure there is no residual contamination on equipment used in the production process. TOC and conductivity provide a comprehensive view of chemical contamination from product carry-over, however often companies are still analyzing cleaning validation samples in the lab, delaying equipment release back into production. Lab analysis of TOC and conductivity also has the potential for introducing human error when isolating samples.
Online TOC and conductivity monitoring with Sievers M9 Analyzers for cleaning validation enables real-time results related to equipment cleanliness, enabling companies to confidently release equipment into production, optimize uptime, remove delays due to QC workflow, and ultimately reduce any human error that may be associated with isolating samples. This enhances their contamination control strategies as they are able to trend and control in real time and make decisions on results in real-time.
Testing for endotoxin and bioburden are an important part of risk reduction for cleaning validation programs, as Gram-negative bacteria can still be present on equipment even after cleaning or sanitization. However these traditional testing methods need to be easier and faster to have utility as at-line or process monitoring tools for cleaning validation. Now, with Sievers centripetal microfluidics for BET (see previous section) and RMMs for bioburden (see previous section), pharmaceutical manufacturers are able to reduce risks related to equipment contamination using instrumentation that is simple to use and yields faster results. Paired with online cleaning validation using Sievers TOC and conductivity analyzers, manufacturers have a comprehensive understanding of their cleaning processes and the ability to make quick decisions to maximize equipment uptime and production.
Conclusion
Developing a contamination control strategy with endotoxin, bioburden, TOC, and conductivity testing can allow for continuous monitoring to optimize uptime and identify contamination earlier in the process. Innovative technologies that test for these parameters align with the guidelines from Annex 1 to enable better process understanding and control, and to minimize the risk of contamination. Sievers Instruments for continuous monitoring and rapid monitoring make it simpler and faster for manufacturers to achieve their CCS goals, ultimately detecting contamination sooner and making it easier to uphold the highest standard of patient safety through quality in the drug manufacturing process.
Author Biographies
Briana Nuñez is a Microbiology Technical Sales Engineer for the Sievers Instruments product line, part of Veolia Water Technologies & Solutions. She was previously the Lead Researcher within the Sievers Instruments Microbiology Center of Excellence in Tucson, Arizona. Briana is responsible for supporting the implementation of automated endotoxin testing in microbiology labs and has participated in research and development of Rapid Microbiological Methods (RMMs) for bioburden analysis. Briana also plans and conducts laboratory experiments, provides training, delivers presentations and product demonstrations at customer sites, and assists in customer support. Briana holds a B.S. from State University of New York at Purchase College in Biology.
Meg Provenzano is the Product Manager for Sievers bio-detection instruments at Veolia Water Technologies & Solutions. She has over 10 years of experience in the bacterial endotoxin testing industry and has held several positions in Quality Control, Technical Support, and Product Management. She is customer-centric and enjoys hands-on problem solving, whether for technical issues, assay assistance, or software. Meg holds a B.S. in Marine Science and Biology from Coastal Carolina University where she focused on Bottlenose Dolphin population research.
Hayden Skalski is the Lead Life Sciences Product Application Specialist for the Sievers Instruments product line, specializing in bacterial endotoxins testing (BET). Hayden has over 8 years of experience in the pharmaceutical industry and Quality Control Microbiology and has presented on numerous topics surrounding endotoxin testing. Previously, Hayden held roles at Charles River Laboratories, Regeneron and Novartis, validating and executing method development protocols for endotoxin testing, providing customer support, troubleshooting and supporting high-volume product testing. Hayden has a B.S. from the University at Albany (SUNY) in Biology.
Kaitlyn Vap is the Life Sciences Lead Product Application Specialist responsible for supporting Sievers total organic carbon (TOC) customers at Veolia Water Technologies & Solutions. She works with companies in the pharmaceutical industry to implement Sievers analytical instruments for the validation of laboratory water and drug products in accordance with global pharmacopeia regulatory standards. As an application specialist, she also explores new and/or developing applications to streamline the process of water and drug product testing. Kaitlyn holds a B.S. in Chemical Engineering from the University of Wyoming.
Veolia Water Technologies & Solutions, Sievers Instruments
Visit our website www.watertechnologies.com/sievers for more information
Subscribe to our e-Newsletters
Stay up to date with the latest news, articles, and events. Plus, get special
offers from American Pharmaceutical Review delivered to your inbox!
Sign up now!