Over the past year, what are some general issues or problems pharm/biopharma companies are dealing with in regard to controlling contamination in their facilities?
Christina Adkison, Cleanroom Marketing Manager, Contec, Inc.: Monitoring and controlling contamination is a huge piece in any pharmaceutical companies’ SOPs. An issue we all have, including pharmaceutical companies, is time. The time it takes to clean and disinfect between shifts and between lots can seem overwhelming. It’s important to remember the time it takes to do something right the first time saves time in the end. For example, disinfectants can leave behind residue. With repeated use, residue can build up leading to contamination problems. Residue is unsightly, but it can also cause a slip hazard and be a breeding ground for contamination. If a disinfectant is used, then is rinsed with a solution or DI/WFI water on a routine basis, the residue is removed which leads to less issues later saving time and money.
Harolyn M. Clow, M.S., SM (NRCM), Manager, Bio/Pharmaceutical Microbiology, Eurofins BioPharma Product Testing: Eurofins has observed an increase in requests for both microbial and viral disinfectant efficacy testing over the last year as a direct result of manufacturing changes in disinfectant formulations and increased scrutiny of cleaning and disinfection processes. Companies face challenges balancing the cost of those studies while ensuring the studies adequately support changes in disinfectant and/or cleaning procedures. Another consistent issue we work on with our clients is ensuring that their cleaning validations are current and adequate as their manufacturing operations change and expand. As contract manufacturing and non-dedicated production lines become more prevalent, companies need these studies to demonstrate that cleaning is effective when changing over manufacturing lines to produce different products, both for removal of active ingredients and control of microbial growth.
Tim Sandle, Head of Microbiology and Sterility Assurance, Bio Products Laboratory Limited: If you look at product recall data, then microbial contamination and sterility assurance concerns continue to remain in the top group of reasons for recall. There’s a similar trend with inspection findings, especially with the finding that ‘sterility assurance is weak…’.
Many of the issues faced in relation to microbial contamination come down to design, such as failing to build in ‘Quality by Design’ into a new item of equipment or with a cleanroom at the project conception phase, or poorly undertaking or reacting to key qualification data, such as sterilizer validation, media fill design, and with conducting airflow visualization studies.
In terms of actual contamination, the recurrent recovery of sporeforming organisms remains a concern. This highlights the need to embed the regular use of a sporidical disinfectant within the contamination control strategy. With non-sterile products, there is growing awareness of the need to define and consider exactly what organisms might be objectionable, by assessing the product characteristics and patient population – regulators are no longer going to spoon feed companies, they need to develop their own assessments. This may require variations to test methods in order to detect the specific organisms of concern.
Benoit Limon, Associate Product Manager – Bioprocess Applications Specialist, Floor Model Centrifuges, Laboratory Products Group, Thermo Fisher Scientific: Biologics are subject to strict requirements with regards to their purity and safety for patient use. During process development and early phase trials, it is critical to demonstrate not only the efficacy of the product for the intended condition, but also to ensure the product is not causing any adverse effects. In line with current Good Manufacturing Practice (cGMP) guidelines, biopharmaceutical manufacturers define acceptable limits for key product characteristics at each step of the process, and perform all necessary measurements to demonstrate the product is pure and safe.
Controlling the sources of contamination has always been a key challenge to overcome in cGMP-compliant biopharmaceutical manufacturing facilities. In response, standards have been established to minimize the potential of airborne contamination of the biological materials, while also protecting researchers handling these dangerous substances. These standards are continually evolving, driven by the growing need for more rigorous contamination control.
Jessica Rayser, Product Manager of Accugenix® Services, Charles River Laboratories: Over the past year, there have been significant changes to regulations, with the Annex 1 “Manufacture of Sterile Medicinal Products” revisions possibly being the most significant. These revisions will enforce stricter guidelines for pharm/biopharma contamination control strategies. Manufacturers will have to be adept, flexible, and forward-thinking to implement these changes.
As new types of therapies, such as cell and gene therapies, are introduced into the market, what do pharma companies have to do to adapt their contamination control strategies?
Adkison: It’s important to remember – not all cleaning products are suitable for every market. A disinfectant that is used throughout a facility, may not have a fast-enough contact time or a mop may be a bit too large for that application. It can seem overwhelming to navigate. Therefore it’s important to find a provider that can supply a multitude of products for various areas in the facility. Don’t be afraid to ask the tough questions – is a sterile product ok or is a certified low endotoxin product needed? If working in a smaller environment such as an isolator, is a cleaning tool being used to reach the difficult corners? What is the contact time of the disinfectant and do we need to revalidate? Pharmaceutical companies are not “cookie cutter” and the contamination control solutions shouldn’t be either.
Heather Beyer, Ph.D., Manager of Viral Safety Testing Services, Eurofins BioPharma Product Testing: A risk evaluation ensures companies have a complete contamination control strategy, including supporting disinfectant efficacy evaluations, environmental monitoring programs, and cleaning studies. Novel therapies often create unique challenges with contamination control due to condensed times from manufacture to patient dosing. Rapid testing for mycoplasma, bioburden, and sterility are often requested instead of using traditional methods. These rapid methods decrease the time to result by 50% for sterility and more with the rapid mycoplasma test which impacts environmental monitoring’s role. With condensed production timelines, historical approaches to environmental monitoring programs require adjustment. Manufacturers must build in more control up front since they cannot always evaluate environmental monitoring that occurred during batch production before product release. Demonstrating that controls and cleaning processes maintain the production environment in the required state becomes more critical. Using Environmental Monitoring Performance Qualifications (EMPQ) and particulate or bioburden controls for materials entering the manufacturing area is a common starting point.
For novel virus-based therapies where the product is a virus that can destroy the indicator cells, novel approaches must be used to screen for contamination. Routine assays can be modified by including neutralizing antibodies, testing non-infected control cells, and routinely implementing Next Generation Sequencing.
Sandle: These developments with cell and gene therapies bring with them challenges in relation to contamination control. The processes are relatively small in scale and complex and they are mostly developed through manual processing. To safeguard this, a high technical skill for operators is needed such as a demonstrable competence in aseptic manipulations.
These products are often infused and go to immunocompromised patients. This means the products should be sterile, but the challenge is that the products would be damaged by any sterilization process. To strengthen manufacturing closed process technology, such as the use of single-use, sterile disposable technologies can help to minimize the contamination risk.
The contamination risk is not only from typical cleanroom and human carried bacteria, many aspects of cell culture are also prone to contamination from mycoplasmas and special testing and media are required to assess this type of contamination, such as a rapid method like Nucleic Acid Amplification Techniques.
A key control mechanism is with understanding where the starting materials (such as whole blood) are coming from and knowing their quality. This can be aided by purchasing materials from licensed establishments. With production, there is also the need for multi-product, multi-patient processing, which brings with it cross-contamination risks There are also additional safety considerations in relation to those technologies that require genetic modification by viral vectors.
Limon: With cell and gene therapies, a therapeutic gene is typically capsuled within a biological material vector, which is used to target patient cells to treat the cause of the disease. The consequences of the vector carrying uncontrolled contaminants can be extremely severe. Not only might the therapeutic gene not be able to deliver the desired benefits, but also unexpected, unwanted adverse effects may occur.
During process development for such new types of therapies, there are multiple possible sources of contamination and impurities, which can be down to the nano-size of the gene. In response, biopharmaceutical manufacturers need to adapt their contamination control strategies to ensure new therapies are safe for patients. A key approach to take involves closely monitoring product contact materials to ensure they are not releasing nano-size particles to the respective biological materials. Furthermore, it is important to implement cleaning and decontamination validation procedures to ensure the entire path flow remains sterile at all times.
Rayser: New therapies, such as cell and gene therapies, require manufacturers to think beyond the traditional manufacturing and testing procedures. Manufacturers will be driven by speed and I expect to see a higher adoption rate for rapid methods. Moreover, as these therapies consist of short production cycles and shelf life and often released at-risk, the contamination control strategies are forced to be much more robust and comprehensive.
As a provider of contamination control technologies and services how do you help your clients stay in compliance, especially when they have facilities spread around the globe?
Adkison: Contec has worked to build and maintain a global presence with our wide range of contamination control products and services around the world. We understand one product does not work for each facility in every country therefore we meet with customers, discover their cleaning challenges and needs then present them with a portfolio of options ideal for their specific facility. Contec doesn’t take a one size fits all approach. We work directly with our customers to provide them with a custom solution to help them stay in compliance.
Clow: It’s important for clients to know their applicable regulations. We provide guidance in this area based on our experience with EMPQ work and expertise in contamination control. Our technical management team stays current on applicable regulations by attending conferences and training. Working with a variety of clients across the globe in the pharmaceutical industry for over 25 years allows us to leverage best practices and feedback from regulatory agencies. By partnering with our clients, we help them identify areas where they can harmonize practices across facilities, maximize disinfectant efficacy studies for multiple sites, and support their contamination control efforts through successfully designing and implementing collection strategies that meet their needs.
Limon: At Thermo Fisher Scientific, we are in close collaboration with our global customers and actively listening to their evolving needs. We are continuously developing new products and services to enable our customers to make the world healthier, cleaner and safer. When it comes to life science instrumentation, consumables and services used in the development and manufacture of biological materials in compliance with cGMP requirements, not only do we meet all market standards, but we also introduce forward-looking innovations. Our global network of local service providers ensures products are matched to customer needs, and customers are supplied with products that can bring the most value for their specific applications.
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For example, ultracentrifugation is widely recognized as a powerful technology for delivering increased yields of highly pure biological materials, by separating nano-size particles through density-applied centrifugal forces. For large-scale applications, taking a continuous flow approach enables scientists and researchers to purify and concentrate large volumes of materials within a short timeframe, but at the same time the process introduces a risk of contamination. Controlling that potential risk is of utmost importance and Thermo Fisher Scientific has developed a unique smart technology specifically designed to provide documented evidence of cross contamination-free conditions as these are applied into the sample stream.
Rayser: Just as our clients have global facilities, so do we. Our global presence allows us to streamline the shipment of samples for testing, ensure faster communication, and understanding of client needs. Our microbial identification procedures and libraries are harmonized so clients can be assured of an accurate identification result, no matter which laboratory is used. This consistent and unified approach is particularly important as client materials are shared or moved site to site.
What are some “must have” items a contamination control strategy must have in terms of equipment, services, data collection and analysis, etc.?
Adkison: In many instances, a facility has already been built therefore you work with what you have. It’s important to maintain proper air flow from the more critical areas down to the less critical areas. Cleaning supplies, waste areas and equipment need to be designated to certain areas to prevent cross-contamination. Employee training when it comes to cleaning best practice is crucial for a good contamination control program. Companies, like Contec, offer this service through in-person demonstrations and/or educational videos. It’s also important to have a clear, concise and easy to follow SOP. Without this, it’s allows room for the operator to start interpreting. A good SOP includes clear instructions on disinfectant dwell times on a surface, addresses irregular surfaces and how to clean them, proper wipe or mopping technique and a rinse regimen. It’s also important to have the correct tools. If the environment is small like an isolator or biosafety cabinet, the tools needed will be different than a larger, less critical room. Finally, having a robust environmental monitoring program is important to know if contamination is present in the facility. Performing a risk analysis on the critical processes and products will significantly improve the understanding of vulnerabilities and corrective actions. Knowledge is power to fix a potential problem before it becomes a large issue.
Sandle: First off, as the EU GMP Annex 1 process signals, there is a pressing need for pharma organizations to develop a formal, holistic contamination control strategy. This is a dynamic process that should reflect the site-wide strategy for minimizing contamination control with respect to sterile manufacturing.
There also needs to be investment in more modern technologies, especially those that enable real-time monitoring and which can alert to a potential contamination event. Here we have emerging biospectrophotometric technology, which can assess both air and water systems. Over time the readings from such instruments can be used to equate to probable microbial numbers.
Microbiology labs also need more intuitive tools to enable sophisticated trend analysis; while there are many weaknesses with environmental monitoring, the strength of the activity is with copious amounts of data and trending, and as the data set becomes larger, the only way the big picture can be seen is with trending.
Another key element is the use of risk management, which requires appropriate tools to spot contamination risks and to determine monitoring points. Drawing on Hazard Analysis Critical Control Points (HACCP) concepts, is an example for pinpointing the critical control points that will signal contamination build-up (both microbial and in relation to bacterial endotoxin).
Limon: Process equipment must prevent leakage of biological materials, while also protecting materials from contamination. It is advisable that equipment is operated in a sterilized closed system.
When the materials in question are pathogens, any leakage could potentially be harmful to the operators, posing a biological hazard risk. At the same time, contamination of biological materials may result in the loss of expensive batches that are very costly to replace.
In the case of continuous-flow industrial-scale ultracentrifugation applications for the purification and concentration of biological nano-particles, there are large amounts of high-value biological materials that need to be processed through a sealing unit. The sealing unit is used to seal the rotating and non-rotating paths, and due to high rotational speed, cooling and lubrication of the sealing unit are required. Monitoring the sealing integrity is a key strategy to control contamination.
The Thermo Scientific Sorvall CC40NX Ultracentrifuge Series has been designed to provide documented evidence that biological materials are protected against the cross-contamination risk. When the process path is maintained at a higher pressure than the sealing unit cooling and lubricating utility pressures, and when the pressure cascade is monitored and documented on the batch data report, then the possible root cause for contamination can be controlled, documented and available for further analysis.
Rayser: An often-overlooked contamination control activity is tracking and trending of data. So much work and effort goes into generating data points, but the real power lies in analyzing trends. This enables manufacturers to identify changes in the environment, spot and correct potential problems before they occur, and maintain a strong regulatory compliance stance.
If you had to pick one major issue that will define contamination control strategies over the next few years what would that be? Why?
Adkison: Risk based analysis and environmental monitoring will continue to be key for a facility’s contamination control strategy. The pharmaceutical industry is changing rapidly. As technology grows, so does the market reach into different important sectors such as cell and gene therapy. But these markets are different and require study and evaluation as well as front-end planning and implementation to ensure the correct contamination control strategies are being used. This may include updating SOPs, increased environmental monitoring and purchasing the correct tools to properly clean and disinfect the space. One product does not work in every space and one plan does not work for every market. Care and consideration must take place up front to ensure proper strategy is implemented.
Sandle: Moving aseptic processing fully over to isolators and robotics. This is due to the importance of maintaining a barrier to protect the aseptic zone; because environmental monitoring has such poor detectability; and the ultimate need to exclude people from the aseptic core.
Limon: Any process equipment should be able to effectively control contamination and provide relevant documented evidence with batch traceability. During the audit of a specific batch, reviewing the traceable batch data report, there should be evidence of the contamination risk-free conditions. This is especially important for continuous-flow process equipment with a sealing unit used in biological materials purification for new types of therapies where nano-size impurities matter.
Purification and concentration are among the final steps in the biological materials downstream process – materials have already been processed and controlled through many earlier steps and at a high cost. The purity of biological materials is key to pass quality testing and obtain clearance for batch release. Any contamination, or lack of traceable documented evidence to demonstrate contamination risk-free conditions, can lead to costly batch loss, potentially causing market supply shortage.
On the Sorvall CC40NX Ultracentrifuge Series, the process path pressure cascade ensures contamination risk-free conditions, while the pressure is monitored to document the contamination risk-free conditions with batch traceability.
Rayser: Over the last few years, there has been an increase in FDA warning letters for incomplete root cause investigations. While companies profess their commitment to investigations, oftentimes that is overruled by a hurry to meet their Quality metrics. I think more and more companies will strengthen their contamination control strategy by implementing genomic tools for root cause investigations, like strain typing.