Microbiology Roundtable

Microbiology Roundtable

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

Veronika Wills, Manager Technical Services, Associates of Cape Cod: Over the last year, one of many focuses of the pharmaceutical industry has been ensuring detection of microbiological contaminants (e.g. bacterial endotoxins) with the additional challenge of doing so in a sustainable way. A well-balanced approach to sustainability efforts spanning the 3Rs (Reduce, Replace, Refine) is implemented by many as part of their strategic growth plans, and here at Associates of Cape Cod, Inc. we also strive towards the same. The LAL industry, one of the pipelines feeding into pharma, is expected to be constantly improving. For example, waste and consumption of LAL reagents is being reduced, processes refined and in some situations, alternate reagents used as replacement for LAL. While the LAL reagents do not exactly fall under the definition of animal testing (the LAL industry does not use crabs for testing; only a small proportion of horseshoe crab hemolymph is removed and then later refined into a final product that supports in-vitro testing), there may be other drivers for a replacement of LAL reagents e.g. a sustainable supply chain. It has to be noted, however, that such replacement will have little to no impact on the crab population. In fact there is evidence to suggest that in areas where the populations are managed and LAL manufacturers exist, the horseshoe crab populations are doing much better than where there is little focus.

Dr. Tim Sandle, Head of Microbiology and Sterility Assurance at Bio Products Laboratory Limited: There has been some interesting developments with microbial detection technology. As with most technological waves, developments spring from outside of the pharma sector and then become adopted later (such is the conservative nature of our sector).

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

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

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

A second area of technological advance is with molecular probes, which help to look for specific pathogens in materials. For instance, probe tests for a particular sequence of DNA and small groups of probes can be used to check for specific bacteria or viruses up to the species level.

Christopher Parker, Microbiology Associate Manager at Cambrex: Over the last year, several disinfectants have been discontinued from being manufactured including Vesphene II and LPH II. These disinfectants are commonly used in cleanroom environments as part of the routine cleaning. As a result of the disinfectants being discontinued, new disinfectants need to identified and validated through disinfectant qualifications for each facility that is affected by the change.

Alan Hoffmeister, Senior Global Technology & Market Development Manager, Microbial Solutions, Charles River Laboratories: The rush in some quarters to adopt recombinant alternatives to the proven Limulus Amebocyte Lysate (LAL) assay for bacterial endotoxin testing. Without substantive, statistically meaningful data from testing naturally contaminated samples to prove the recombinant alternative’s equivalence, there is a potential risk to ongoing product quality and patient safety. This could be the most critical issue affecting the industry for the fore-seeable future.

Jeanne Moldenhauer, Vice President, Excellent Pharma Consulting:

  • Reluctance to go to newer, more sensitive detection methods.
  • Reduced budgets due to COVID-19 pandemic.
  • Lack of appropriately qualified people.

Peggy Banarhall, Product Manager, METTLER TOLEDO Process Analytics; Akash Trivedi, Business Development Manager, METTLER TOLEDO Thornton; Jim Cannon, Pharmaceutical Market Manager, METTLER TOLEDO Thornton: Since the FDA announced its Process Analytical Technology (PAT) initiative in 2004, the industry has moved towards online measurement of various critical parameters to ensure overall process control and the resulting quality assurance. This includes parameters such as total organic carbon (TOC) and conductivity for Purified Water and Water-for-Injection. However, the industry has been slow to adopt a similar overall control strategy for detecting microbial contaminants, which would include online rapid microbial methods (RMM) as a complement to the validated method of plate counts. USP and other agencies have highlighted that plate counts are only an estimate of the microbial population in a water system and that RMMs should be used as part of the overall control strategy for pharmaceutical water systems. Alternative microbial methods report a different measurement signal, which does not correlate with the traditional CFU plate count. The industry needs more education and experience with adopting such RMMs and different measurement units, which has slowed the march towards the goal of overall process control which provides various benefits in terms of time, cost and resource savings.

Tony Cundell, Ph.D., Principal Consultant, Microbiological Consulting, LLC: The industry response to the recent EU Annex 1 revision that wisely emphasizes that processes, equipment, facilities and manufacturing activities should be managed in accordance with Quality Risk Management (QRM) principles that provide a proactive means of identifying, scientifically evaluating, and controlling potential risks to product quality, including microbial contamination, will be critical to our efforts to eliminate microbiological contaminants. This is an opportunity for pharmaceutical companies to take a fresh look at the risks associated with microbial contamination and re-engineer their manufacturing operations. Let’s take advantage of this opportunity to improve our sterility assurance levels.

Obviously the COVID-19 pandemic has overturned our lives, seriously damaged the global economy, and threatened the pharmaceutical supply chain. During my self-isolation in the suburbs of New York City I had the opportunity, through my involvement with the PDA COVID-19 Task Force, to co-author a 12,000 word review article entitled Controls to Minimize Disruption of the Pharmaceutical Supply Chain during the COVID-19 Pandemic that was posted on the PDA website as accepted for publication on May 28, 2020 and officially published in the July-August 2020 issue of the PDA Journal of Pharmaceutical Science and Technology. We concluded that as SARS-CoV-2 is a highly communicable human respiratory virus, the largest risk to the supply chain is primarily absenteeism amongst line employees preventing the manufacture, testing, and distribution of drug products and secondly the unavailability of pharmaceutical ingredients, testing supplies and packaging components needed to make these products, not drug product contamination. It was gratifying to find that most of the positions taken in the review article were supported by the industry, as determined by a PDA membership survey, and by the FDA as presented in June 19 2020 Guidance for Industry - GMP Considerations for Responding to COVID-19 Infection in Employees in Drug and Biological Products Manufacturing.

Although, most of us are not directly involved with SARS-CoV-2 vaccine production, we are all cheering from the sideline. In the interests of innovation in vaccine development, I am hoping that the new mRNA approach, taken by at least two companies, will be amongst the winners.

Dr. Michael Miller, President, Microbiology Consultants, Owner of rapidmethods.com: Time to result. We continue to use 19th century methods for the testing of contaminants within manufacturing areas, in-process samples and finished product. Advances in rapid microbiological methods have come a long way, and the industry now has the tools to employ faster detection, enumeration and identification technologies. Real-time detection of contaminants in air and water are currently available, and next generation Raman spectroscopy technologies are being developed that can detect, quantify and identify single cells in a matter of minutes.

David Jones, Director of Technical Marketing and Industry Affairs, Rapid Micro Biosystems: Even before COVID-19 the manual nature and the length time for QC Micro results were challenging for biologic manufactures. Now that companies need to utilize all of their capacity waiting for results or having to rely on a labor intensive in person process has become an even greater problem. Detection of potential contaminants from the production environment is a function of the site’s sampling plan and frequency of sampling. But even the best and most frequently sampling plan is hindered by having to wait 5-7 days for results. This causes a significant time lag between when the site becomes aware they may have a contamination issues and this is compounded by the tremendous back log of results to be analyzed to obtain tracking and trending data needed to interpret recurring issues. The ability to detect potential contaminants faster and recognize trends sooner requires a much more automated, streamlined process. With the time lag associated with manual methods, there is difficulty determining root cause or activities which resulted in contamination simply because no one can remember exactly what they were doing seven days earlier or even longer. The workload per tech is overloaded and they many times struggle to simply complete tasks with no remaining time to think through an issue and resolve. Detection of potential contamination hotspots earlier in the process is critical to eliminating contamination rather than awaiting final sterility results as it is beyond fixing at that point.

Azita Kazemi, Microbiology Manager, SGS North America, Inc.: One of the critical industry issues is effective cleaning procedures and analytical methods must be available to determine the CFUs in rinsates prior to the manufacturing campaign and/or in the finished product.

A cleaning operation, followed by drying, must take place as soon as possible after production has stopped, irrespective whether a succeeding product is scheduled for that specific equipment. This prevents possible build-up of microorganisms in the equipment.

Also, products purchased from suppliers of active ingredients, intermediates and/or raw materials must meet all quality criteria, including those related to prevention and/or control of microbial contamination.

Michelle Neumeyer, Life Sciences Product Applications Specialist for the Sievers line of analytical instruments at SUEZ – Water Technologies & Solutions; Dave Wadsworth, Global Product Manager, Bio-Detection at SUEZ – Water Technologies & Solutions: Monitoring endotoxins in ultrapure water, in process components, and final drug product continues to present significant issues within the industry. Most notably is the manual and cumbersome assay setup process, which presents significant opportunity for error, thus leading to costly retests. Additionally, data integrity gaps with manual test methods such as gel-clot, or inadequate software with a kinetic method, continue to impact businesses’ abilities to detect endotoxins routinely with complete confidence.

Mike Dingle, Field Application Specialist, TSI: Operating under a pandemic has obviously been a critical issue for all industries, and this industry is no different. Those whose job it is to detect and eliminate microbiological contamination are probably one of the best to understand and deal with this. In fact, the encouraged behaviors that are new to most are commonplace practices for those in the world of contamination control. With that said, even these professionals have likely needed to make some adjustments to their work routines as well.

Efforts to limit contact between personnel has led to such practices as operators working split shifts and management working from home as much as possible. This has amplified the issues associated with the extremely manual nature of traditional microbiological methods. If these practices are to continue, the drive to explore and implement more automated test methods and electronic systems will accelerate. These will reduce crowding in the lab, while also improving data integrity and accessibility.

Paula Peacos, MS, Senior Consultant, ValSource, Inc.: The increased focus on risk-analyses (as well as the quality of those analyses) and holistic facility contamination control programs has required microbiologists to increase their baseline knowledge of the processes they support. Identification of the critical contamination control points throughout the process has prompted better, more thoughtful design of supporting control programs such as EM, gowning, cleaning and disinfection, facility design, in-process testing programs, training programs, etc. All of this in turn allows for more proactive measures to be employed and can also improve the success of microbiological root cause analyses during investigation by identifying the areas of highest risk.

Cell and gene therapies have emerged as a “hot topic” in the industry. What are some unique microbiological challenges associated with these products?

Sandle: The critical nature of gene therapy means that it is essential to keep cells free from contamination by microorganisms. The problem is that the risk of microbial contamination is high, reflecting the complexity of cell production procedures, which typically involve multiple stages. Each stage requires a level of accuracy and the highest standards of environmental control.

A proactive approach to minimizing contamination is through maintaining an aseptic environment, and this is best achieved through the adoption of barrier technology (such as isolators).

As well as contamination from bacteria and fungi, viruses present a significant risk. It is important that manufacturers develop safety strategies to reduce the risk of virus contamination and implement these based on an understanding of the main viral risks (such as enveloped or non-enveloped viruses) and the appropriate inactivation methods which will eliminate the viruses but, at the same time, not damage the product.

Best practice tips are with the selection of appropriate starting and raw materials; testing cell banks to ensure they are free from detectable viruses; and manufacturing steps designed to remove and inactivate undetected adventitious and endogenous viral contaminants.

Parker: The challenges of working with cell and gene therapies include the short expiration dates and susceptibility for contamination of cell lines. Many companies are turning to rapid microbial testing to combat the short expiration dates of these products. A robust environmental monitoring program and aseptic training are required to overcome the challenges of working with these cell cultures.

Sahil Parikh, Marketing Manager, Microbial Detection, Charles River Laboratories: The most frequent challenge with delivering these emerging therapies to patients is their short shelf life. Since these therapies must be administered to the patient, sometimes within 24 hours, they are often done so at risk, ahead of the final results of contamination testing, such as final sterility. While every effort is made to ensure the product is aseptic and free of contamination, the patient is still at risk. Therefore, providers of these therapies should take advantage of confirming the safety of these products as quickly after administration as possible so that healthcare providers can treat a potential infection. Additionally, these types of drug products have compositions different than traditional small, or even large, molecule products. Rapid microbiology can provide solutions to these challenges if they are selected carefully and have a wide product compatibility range. Rapid sterility testing can reduce the fourteen days of risk a patient is exposed to down to 5-7 days, eliminating over a week of unnecessary exposure to potential infection.

Dave Nobile, Technical Services Manager, Contec, Inc.: Cell and gene therapy manipulation is overwhelmingly performed within the confines of a minienvironment such as a biosafety cabinet (BSC) or isolator. This personalized medicine approach requires that each manipulation is dedicated to a single patient, with no product or materials unrelated to that patient in the minienvironment during each manipulation.

For volume production this requires many mini environments that must be cleaned and sterilized between each manipulation event. This can mean cleaning, disinfecting, and stabilizing each mini environment multiple times a day. Such frequent interaction between technician and mini environment significantly increases the risk of microbial contamination of the mini environment from the usual sources; the technician, garments, gloves, wipes (used for cleaning), solutions, and the necessary materials and hardware brought into the mini environment for manipulation.

While sterility and control of these potential contaminant sources is critical, the sheer volume and repetition of cleaning and disinfecting the mini environments between each manipulation event can be daunting, posing risks to microbial control due to complacency, deviation from protocol, or both. For robust and effective microbial control under such frequent activity, it is critical to create validated standard operating procedures (SOP) in which the entire cleaning/disinfection protocol is as simple and efficient as possible, and that operators have the best tools and materials to execute the SOPs most easily.

Harolyn M. Clow, MS, SM (NRCM), Manager, Bio/Pharmaceutical Microbiology, Eurofins: Rapid microbiological testing is crucial for cell and gene therapies due to the pace of production and patient needs. Implementing and qualifying rapid methods that detect microbial contamination at the same or greater sensitivity as conventional and currently accepted tests can be challenging due to the various matrices and potential interferences from inherent materials in the products. Interactions with reagents used in the rapid testing may also need to be considered. Some manufacturers currently require suitability on each produced therapy due to the unique patient variable, i.e., every lot is a different “formulation.” Establishing a robust suitability for the stable matrix can demonstrate the variable components do not impact recoveries of microbial contamination when using conventional or rapid methods, allowing more rapid testing without concurrent suitability to decrease time and cost.

Moldenhauer:

  • Many of these therapies are specific to individuals, resulting in small batch sizes. This makes it difficult to have appropriate samples to do all the testing that might be desired or needed to resolve issues.
  • Reluctance to go to newer, more sensitive, rapid, or alternative methods.
  • Keeping personnel motivated to stay at a company. For example, it is easier to change jobs rather than get promotions or salary advances that employees expect.

Barnarhall, Trivedi, Cannon: The industry has seen a tremendous increase in such innovative therapies, off ering hope of recovery to countless patients. However, a number of such therapies require a turnaround time of 2-4 days from extraction to re-injection of cells into the patient. To reduce risk of contamination during such a process, plate counts fall short as the incubation period is at least 5 days to get results. This requires rethinking the control strategy completely, to ensure the process is always under control thus reducing risk of contamination. RMMs, including for the water used for the process, are key to this overall process control strategy. While plate counts would still give a confirmation about the water quality at the end of the incubation period, knowing that the process is under control using the measurements from the RMMs allows the industry to minimize the risk to releasing product within the required turnaround time. The needs of cell and gene therapy products tell us that innovation in patient treatments requires innovation in manufacturing, processing and monitoring of raw materials.

Cundell: Cell and gene therapies have a seemingly unlimited potential for addressing unmet medical needs. Microbial contamination, i.e., the absence of mycoplasma, bacteria, fungi and viruses, is a critical quality attribute of these unique products. Given the multiple steps from donor selection, cell harvesting, transformation and expansion, formulation, packaging, shipment to administration, microbial contamination risk identification and mitigation are critical activities. To develop a more holistic approach to mitigating microbial contamination in Advanced Therapeutic Medicinal Products (ATMPs) I co-authored a review article entitled Risk Assessment Approach to Microbial Contamination Control of Cell Therapies published in the May-June 2020 issue of the PDA J. Pharm. Sci. & Tech. Why is getting it right important? Peter Marks, M.D., Ph.D., Director of the FDA’s Center for Biologics Evaluation and Research stated: “As the regulators of these novel therapies, we know that the framework we construct for product development and review will set the stage for continued advancement of this cutting-edge field and further enable innovators to safely develop effective therapies for many diseases with unmet medical needs.”

Miller: The need to quickly release these products due to short shelf life and/or the ability to administer the therapies in patients as rapidly as possible. Furthermore, many new advanced therapy medicinal products (ATMPs) are manufactured in very small volumes which do not allow batches to be tested for sterility according to current compendial requirements. For example, Tables 2 and 3 in USP chapter 71 would require an amount for sterility testing that would leave too little drug for a positive clinical outcome. Fortunately, the compendia and regulatory authorities have addressed these challenges with updates to recommended testing strategies and policies. The reader should refer to USP chapter 1071 (Rapid Microbial Tests for Release of Sterile Short-Life Products: A Risk-Based Approach), Ph. Eur. Chapter 2.6.27 (Microbiological Examination of Cell-Based Preparations), 21 CFR 610.12 (Amendments to Sterility Test Requirements for Biological Products), FDA’s 2020 guidance on cell therapy (Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications), the European Union’s 2018 guidance on ATMPs (Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products), and the guidance provided at http://rapidmicromethods.com.

Jones: The microbiological testing for cell and gene therapy manufacture has been an interesting challenge for the industry and regulators. The requirements vary as to components of the process. The viral vectors can be mass produced and bottled and stored frozen so manufacturing and testing mimics standard biologic process testing. The patient product however usually has a critical shelf life and should be “Sterile” for administration to the patient. The pressure is on to make a clean product as often the patient will not survive long enough for a second round in the case of a failed sterility test. Microbial methods that allow faster enumeration for raw material, in process and EM samples in <1-2 days would allow QC to determine the risk of contamination in the final product so it can be released at 3-5 days if still negative with lower risk. There has been discussion on whether the product sterility test needs to be for sterility or can have a higher specification to account for what would be an “infectious dose of bacteria”. Levels of <100cfu have been proposed. In that scenario a sterility test that enumerates contamination would be required rather than the traditional presence/absence test.

Kazemi: Cell and gene therapy product manufacturers face the challenge of microbial control. Manufacturing requires a fully aseptic process with no sterilization. The heat, gas, or radiation associated with the sterilization process will kill immune cells whereas sterile filtration will remove immune cells. The final product usually has a very short shelf life and thus presents a significant challenge with respect to traditional safety tests such as Mycoplasma (agar/broth) and sterility. Alternatives are respectfully, PCR based Mycoplasma testing (same day), and rapid sterility in automated microbial growth systems (~7 days), neither of which are approved by the FDA, and discussions should be had apriori with appropriate justification, and supporting data.

Dingle: The manufacture of cell and gene therapies can vary greatly, and they all come with their own special set of challenges. One challenge these processes tend to share is that they must be performed aseptically throughout because there is no sterilization method that can be used that will not also render the product ineffective. To add to that challenge, the final product may need to be administered to the patient prior to the availability of results if traditional, culture based, microbiological test methods are employed.

Emerging technologies such as gloveless isolators and rapid, or even real-time microbiological detection systems, can mitigate many of these concerns. Viable particle detection using real-time technologies (non-growth based) can assure environmental control without introducing risk through human intervention. However, as with all new technologies, they come with their own challenges involving validation and regulatory acceptance.

Peacos: One of the most challenging issues in my opinion is the exceedingly short turnaround time for some of these processes, especially some of the autologous treatments and therapies which must be administered to the patient as soon as possible after production. This generally requires the use of rapid methods for critical microbiological tests such as sterility. However, some critical controls such as EM still take 5-7 days for results to be obtained. Identification of any isolates recovered takes place after that. Shipping samples to a third party for processing increases that time. Many of these processes are also still very manual in nature, requiring very robust and proactive contamination control measures to be in place, especially as many of the production turnaround times are so short.

The rapidity with which new technology in this area is emerging is also pressuring regulatory bodies and the industry to rapidly determine and publish new regulatory and guidance documents to ensure the necessary controls and standards are in place. For example, many of these products have a very small batch size, requiring innovative sampling and testing strategies to ensure accurate and reliable results, which recently issued guidance documents have helped to address.

What are some must have essentials that have to be incorporated into a microbiological monitoring program to ensure effectiveness?

Wills: Over the last year, one of many focuses of the pharmaceutical industry has been ensuring detection of microbiological contaminants (e.g. bacterial endotoxins) with the additional challenge of doing so in a sustainable way. A well-balanced approach to sustainability efforts spanning the 3Rs (Reduce, Replace, Refine) is implemented by many as part of their strategic growth plans, and here at Associates of Cape Cod, Inc. we also strive towards the same. The LAL industry, one of the pipelines feeding into pharma, is expected to be constantly improving. For example, waste and consumption of LAL reagents is being reduced, processes refined and in some situations, alternate reagents used as replacement for LAL. While the LAL reagents do not exactly fall under the definition of animal testing (the LAL industry does not use crabs for testing; only a small proportion of horseshoe crab hemolymph is removed and then later refined into a final product that supports in-vitro testing), there may be other drivers for a replacement of LAL reagents e.g. a sustainable supply chain. It has to be noted, however, that such replacement will have little to no impact on the crab population. In fact there is evidence to suggest that in areas where the populations are managed and LAL manufacturers exist, the horseshoe crab populations are doing much better than where there is little focus.

Sandle: Environmental monitoring programs need to be well-thought and planned. It’s important to establish what the frequency of sampling will be and what this will be based on (such as biasing the program towards areas where open processing occurs). Care also needs to be given to sample site selection, and this should be based on established risk methodology (such as HACCP).

The essentials also include thinking about the different vectors of contamination, such as from people, water, material and transfer and so on, and what the most appropriate methods will be in relation to the contamination transfer points. Airflow visualization can assist with this.

Attention also needs to be given the most appropriate agars and incubation regimes (temperature and time combinations), especially where dual temperature incubation is undertaken.

Overall program effectiveness needs to be gained from regular review. Has the room design changed, for example? Are there new shift patterns? Is a different product being processed? Such questions can prompt the necessity of undertaking a review.

Parker: An effective environmental monitoring program requires an adequate risk assessment to determine the greatest areas of vulnerability for the facility. Environmental monitoring samples provide a snapshot in time of the cleanroom environment and trending over time is required for an accurate assessment of the state of control.

Parikh: Rapid microbiology has been a must-have essential for a comprehensive and efficient microbiology monitoring program and quality system. The industry, by and large, has been slow to adopt rapid detection methods, even though many industry drivers such as data integrity have demonstrated their value. Moreover, increasing speed-to-patient and reducing inventory holding costs have also been drivers, but have certainly moved up in priority as prominent and key drivers this year. Increasingly, pharmaceutical manufacturers have come to realize how rapid methods can ensure business continuity in the face of increased market demand, staffing limitations, and the need to reduce operating costs, all while ensuring their products are 100% safe for use. We have been working closely with many organizations to validate rapid detection systems quickly and efficiently over the last year, as well as support current customers in expanding the use of their current systems. These organizations have been able to adapt with changes in the industry, their patients, and internal organizational restructuring by relying on their rapid detection systems to deliver faster results and improving speed-to-market, inventory, and the burden on their quality control laboratory.

Clow: An effective microbiological monitoring program consists of more than the physical collection of samples to detect contamination. An effective program uses chemical and microbiological cleaning validation to ensure cleaning and disinfection agent residuals are consistently removed or reduced to levels that will not be inhibitory to the recovery of microorganisms when standard cleaning methods are executed. An end-user disinfectant efficacy study provides evidence of the relative effectiveness of selected disinfectants on the types of expected or recovered microorganisms in the facility. The physical environmental monitoring collection events then act as sentinels to confirm the continued effectiveness of the cleaning agent, cleaning procedures, and frequency of cleaning to maintain the cleanliness level desired. This three-pronged approach allows more complete assessment of possible contamination sources and effective remediation steps when unexpected environmental monitoring excursions are observed.

Moldenhauer:

  • A system for tracking and trending of data in a timely fashion, so that one can respond to issues.
  • Qualified or validated methods.
  • Earlier detection methods.
  • Management support.
  • Qualified personnel, e.g., understanding pharmaceutical microbiology.

Barnarhall, Trivedi, Cannon:

  • Overall control strategy for processes, to drive home quality by design and lean quality principles. Such process control strategies would include traditional methods as well as RMMs, to provide continuous monitoring and control.
  • Increased sensitivity and faster response time, in keeping with the evolving needs of the industry as it launches new therapies.
  • Continuous online monitoring of all parameters, including microbiological monitoring, to have a full picture of the health of the process.
  • Definition of proactive and quick steps, relying on RMMs’ output, to mitigate issues before they occur.
  • Corporate strategies and planning should include capital investment needed to improve quality by design and the cost of quality, including RMMs. This was the intent of FDA’s Process Analytical Technology initiative, to help the industry meet the challenges new therapies bring.

Cundell: The pharmaceutical industry must be aware that it is facility design and operation, validated sterilization processes, and aseptic practices not microbiological monitoring that prevents microbiological contamination of our products. Microbiological monitoring programs should be viewed as tools to confirm the effectiveness of our controls and detect any adverse trends. Methods employed for air, surface, and personnel monitoring have serious limitations in terms of microbial recovery, analytical capabilities, and timeliness to obtaining the results.

The recommendations contained in USP <1116> Microbiological Control and Monitoring of Aseptic Processing Environments to track isolation frequency and not numerical alert and action levels is good science and is slowly gaining traction in our industry.

New monitoring technologies especially laser-induced fluorescent particulate monitoring that can provide a stream of data have a huge promise and should be viewed as a process analytical technology. Transitioning from monitoring once per shift to continuous data collection requires we do not over react to the occasional monitoring excursion with emphasis on overall environmental control and the recognition that some interventions may potentially contaminate our operation and product associated with these excursions should be isolated and, if necessary, rejected.

Jennifer W. Vaval, Senior Laboratory Operations Manager, Nelson Laboratories Fairfield, Inc.: Environmental monitoring should be established in the laboratory. This formal program should clearly define the expectations and evaluate all circumstances involving the microbiological quality of the processes. The amount of documentation and tracking should be clearly defined per the SOP and the regulating authority (ie. International Standards Organization (ISO)). Each technique used must be validated to make sure that the adopted method/procedure accurately provides the desired information and allows for trending and traceability.

Miller: The ability to trend data and to move toward alternative methods for environmental monitoring. USP chapter 1116 is an excellent resource for recommendations on trending EM data rather than applying absolute limits. Additionally, the revision to Annex 1 proposes that rapid or automated monitoring systems should be considered to expedite the detection of microbiological contamination issues and to reduce the risk to product. In fact, the revision notes that the types of monitoring methods listed in the table for viable particle contamination (i.e., air samples, settle plates, contact plates and glove prints) are examples only and that other methods can be used. Furthermore, Annex 1 clarifies that the action limits in the same table refer to the colony forming unit (cfu), and that if different or new technologies are used that present results in a manner unlike the cfu, the manufacturer should scientifically justify the limits applied and where possible correlate them to the cfu.

Jones: A key component to an effective EM program is the speed to data review. The use of manual input of microbial data to Excel spreadsheets and monthly review is an imperfect way to either determine facility trends or to implement remedial action in a timely manner. To be effective the testing needs to be performed using a rapid microbial method that automatically downloads the results to a software package such as MODA that can analyze the data and show hot spots or trends in near real time. Having the excursion data pushed to the decision makers immediately should facilitate fast responses that minimize more serious events.

Kazemi: According to 21 CFR 211.113(b), you must begin with a well written Environmental Monitoring Plan since the real value of a microbiological monitoring program lies in its ability to confirm consistent, high-quality environmental conditions at all times. The procedure must be presented clearly for easy understanding of personnel performing environmental monitoring. Training is a key point to prevent microbiological contamination that, in some cases, may be the cause of human error in the manufacturing and testing laboratories.

A crucial element in an effective EM procedure is to determine the correct sites for sampling, the frequency of sampling, and right testing methods such as contact surface sampling and swabbing of difficult to reach surfaces. The program should have well-presented trending information that will be a guide for tracking the contamination path.

Routine testing should be carefully determined to present meaningful information during normal manufacturing hours, and a data library of the facility’s typical recovered microorganisms provides helpful data for OOS investigations. It is very important to set the correct alert and action levels of contamination. Therefore, appropriate actions need to be taken every time when the specifications are reached.

Neumeyer and Wadsworth: From a purified water monitoring perspective, using technology that reduces human interaction with sampling and analysis has greatly increased sample integrity and process efficiencies. For example, when testing for total organic carbon and conductivity in purified water, some instruments can 1) do simultaneous testing of both quality attributes from a single vial, and 2) automate the analysis with autosamplers and software. Online TOC and conductivity analysis is another way to reduce or eliminate sampling, laboratory analysis, and human errors. Online analysis gives the highest level of control and compliance of a purified water system with real-time TOC and conductivity data.

Just as with TOC and conductivity, reducing human interaction and the associated variability with endotoxin detection is a fantastic way to ensure effectiveness. By implementing an endotoxin detection system that reduces human errors by simplifying and streamlining assay setup, laboratories can reduce risks and improve operational efficiency. Of course, it is imperative that any automated system be fully validated and remain fully compliant.

Dingle: The basics of what goes into a microbiological monitoring program is straightforward and well-understood, but what makes it effective or not is how it is implemented. The key to an effective monitoring program is to establish the program based on risk to product and patients, not strictly to meet the regulatory requirements. The program must be able to demonstrate the manufacturing environment remains in adequate control so as not to put product at risk. The GMPs, along with all the other standards and guides, provide a good start, but it is impossible for them to be prescriptive enough to assume that compliance will guarantee effectiveness. Recognition of this can be seen with the increased focus on risk in the draft updates to Annex 1.

Another important component of an effective monitoring program is to make sure that procedures, personnel, systems, etc. are in place to assure that data is reviewed and trended in a timely manner. A very well thought out program that does a first-rate job of collecting all the right data immediately becomes ineffective if no one notices an excursion or adverse trend in time to do something about it.

Peacos: There are two major items that are critical to the success of the EM program. First is a sound program design based on an end to end process-based risk assessment. Critical points in the process where contamination can enter must be properly identified, and the appropriate EM measures applied. The EM program must also be monitored for its efficacy and adjusted as needed, when needed.

Second is a robust trending program. Again, program design is critical to obtain the most useful information. Detailed and robust data analysis is essential. The resulting trending report should be much more than a simple presentation of the data collected from one interval to the next. A good trending program allows the microbiologist to identify and mitigate issues before they become problems as well as to identify opportunities for improvements in supporting programs.

Both of these elements have a huge impact on the success or failure of the larger facility contamination program.

When designing new, or renovating older facilities, how important is the cooperation between equipment vendors, microbiology technology providers and sponsors? What advice can you offer to make this relationship successful?

Sandle: The aging pharmaceutical facility is something gaining regulatory attention. As newer pharmaceutical manufacturing has been moving to countries where labor rates are lower, this has resulted in many facilities in higher-income countries receiving less attention and such ‘aging facilities’ go on to have operational issues. Such issues include struggling to adapt to new processes and the problems associated with weaker fabric.

The extent of the problems of aging facilities means that different parties need to come together. If a new surface is being fitted for example, the microbiologist will need to assess this surface in relation to disinfectant efficacy studies, for example. If new equipment is to be fitted, it may need to be assessed for particle generation and hence overall environmental impact. Further with equipment, consideration also needs to be given as to how the equipment will be cleaned and sanitized and how this will be assessed.

Parker: A good working relationship with your stakeholders and supply chain is vital when designing new or renovating older facilities. To have a successful relationship, there must be an understanding and forecasting of events so the vendor can meet the needs of the facility. The vendor should also be flexible as there are always unpredictable situations that can arise and need action in return. Understanding the importance of meeting timelines is important for both the facility as well as the stakeholders involved.

Parikh: Cooperation and collaboration between equipment vendors and their customers, especially in today’s business environment, is not just important: it is critical. Organizations like Charles River, who provide quality control testing equipment, must truly act as partners for their customers. Quality control solutions, such as rapid microbiology testing equipment, must be supported to routine use, not just to the point of sale. This involves supporting and providing additional solutions for validation, which we now offer, which is always necessary with a new instrument, but has seldom been supported by the supplier. We believe that this paradigm needed to change, and as suppliers and experts in these technologies, the burden can no longer be solely placed on the customer. That being said, we advise quality control laboratories to inquire about what support offerings a vendor can provide to ensure a newly purchased instrument can go into routine use as quickly as possible and supported year after year. This is the true measure of a successful working relationship.

Nobile: Whether designing new or rehabilitating an existing facility, cooperation as well as coordination between the designers, equipment suppliers, construction contractors, and the contamination control engineers/microbiologists is critical. When done effectively, the result is a facility that operates most efficiently, is easier to clean and maintain, and is easier to keep under microbial control over a much longer service life.

All too often, facilities exhibit the result when such coordination is absent: room layouts and equipment configurations that are inefficient or simply not usable, wall and floor materials that are more difficult to keep clean, panel seams that fail prematurely, poorly planned piping and electrical lines that require more time and effort to clean and maintain, return air vent louvers that are impossible to clean reliably, and manually operated doors and lights to name just a few issues.

Cleanliness requirements in pharmaceutical cleanrooms have become more stringent at the same time labor and other costs to maintain the cleanliness and microbial control in cleanrooms have increased. Influencing these facility costs is best done at the outset of the design/planning process. Design, layout, and equipment and systems choices made early, with knowledgeable stakeholders involved, will result in facilities that enable the lowest cost and most efficient cleanroom operation, ease of maintenance, and longest service life possible.

Clow: Cooperation and collaboration are essential. Clear communication and prior planning is more essential. By ensuring that clear communication is flowing between all parties, and having effective planning in advance, facility validation programs related to new designs and renovations will progress more smoothly. Be clear on roles and expectations of each party. Listen to your vendors and providers and also consider their business expertise and suggestions to make your project more efficient. Incorporate multi-way agreements, if feasible, so vendors and providers can communicate and coordinate activities to more quickly meet project needs and provide sponsors with suggestions. Plan as far ahead as possible with your providers to ensure all items have been thoughtfully considered, including what actions to take if steps are delayed or things go wrong. If everyone knows the purpose and end goal, vendors and providers can more rapidly identify issues that require adjustment to plans so they can stay on target. Giving everyone the bigger picture and allowing vendors and providers to be active in ongoing planning so they can rapidly make necessary adjustments, increases the chances of success for all.

Moldenhauer:

  • Vendors need to learn more about how their equipment will be used at the site as well as understand the needs of the company, e.g., validation support, system needs, issues with the types of products made, and the like.
  • Companies should develop User Requirements that clearly define ALL the requirements that must be met for the company to successfully use the system.
  • Validation and Implementation really requires joint effort and work. Both groups need to work together to develop pathways to achieve the desire validation result.
  • Vendors for new technologies need to be honest, especially about throughput and how to achieve the throughputs that they claim.

Barnarhall, Trivedi, Cannon: The relationship between these three entities is essential to move the industry forward and collectively improve our product offerings, processes and raw materials. Equipment vendors and microbiology technology providers need to understand industry trends and be ready to provide solutions to the stakeholders’ needs when they implement new processes. At the same time, stakeholders should involve the other entities at an earlier stage and leverage their expertise to understand new product developments, technology and improved methods. Stakeholders should be open to implementing such methods, in their quest to continuously improve quality, reduce analysis time and increase cost savings. Participation in the industry meetings by various organizations like ISPE and PDA will help all entities to align on industry trends. Close collaboration and educational exchange between the entities, not unlike that conducted by SME’s (Subject Matter Experts) with pharmaceutical engineers regarding the state-of-the-art for system design, would help stakeholders learn about and plan for adoption of improved methods. This on-going collaboration is essential to moving our industry forward.

Cundell: With facility design, construction, and commissioning, the keys are corporate sponsorship, project management, and teamwork. Late in my career at Schering-Plough I participated in the construction of a new non-sterile global clinical supply manufacturing facility in Summit, New Jersey. The facility was modular, designed by a Swedish company, constructed in Poland, shipped, and assembled in New Jersey. Decisions had to be well considered, timely and final. This provided us with focus and a sense of urgency. The in-process microbiology laboratory was constructed connected to the manufacturing facility and samples arrived via a pass through. My R&D microbiology group was kept informed with the overall progress of the project and was engaged on a need basis on facility design, utilities, equipment purchase, and commissioning and process and equipment validation. Key milestones were celebrated and the project was brought in on schedule.

Jonathan Swenson, B.S. SM(NRCM), Sr. Laboratory Operations Manager, Nelson Laboratories, LLC: It is important to find the right team to have a successful build. Having vendors and consultants that fit your communication needs is vital to reduce the number of missteps. The last thing you want to deal with is getting a piece of equipment that won’t fit through your laboratory doorway or dealing with an incubator that won’t stay in range because the room is too cold during the winter.

Understanding the available technology, your current needs and more importantly looking at future growth before you finalize plans will save you time with last minute changes and frustration. For example, if your current benchtop pure water system is near capacity you should review the return on investment for a larger dedicated system rather than planning on buying multiple benchtop systems. This approach will help you from dealing with an equipment spend approval after the budget has already been finalized.

Miller: The relationship between manufacturers and suppliers is of the utmost importance. This should initially be achieved by putting a robust and formal contract in place detailing each party’s responsibilities, commitments and expected milestones for the project.

Jones: It is critical that vendors or technology providers becoming an integral part of this new design or renovation provide insight early in the process to ensure designs and layout accommodate not only the dimensions required for their equipment but the additional requirements specific to their product. Having to retrofit a new building with items overlooked in the design will not only add cost but will delay startup as well. Something as simple as placement of electrical outlets needed for equipment to accessibility to Ethernet cables, anything overlooked becomes critical as they struggle to meet their deadlines. The vendor should work to be included in projects from the beginning with walk-thru visits and blueprint reviews to ensure success while providing your customer with the guidance they need. Listening to the customer’s overall goal and having them walk through how things will work will allow you to make suggestions on their workflow design based on your experience with other site buildouts or current customer layouts.

Kazemi: Having positive vendor and equipment provider relationships goes a long way in deciding the outcome of your project. SGS recently converted a 19,500 square foot manufacturing facility into a modern, well equipped microbiology facility complete with ISO 6 Cleanrooms and ISO 8 laboratories under state-of-the-art HEPA controls. Proper vendor resource management was a key factor in the completion of the building renovation on time. Companies should hold regular review meetings to foster good communication, listening and adapting to changes; asking for vendor feedback will help avoid potential problems. Monitoring the project’s KPIs through regular communication allows both parties to stay on course.

Neumeyer and Wadsworth: It is extremely important to have communication and coordination in the very early stages of a project. This allows for the correct implementation from the beginning, rather than having to retroactively implement what is required. For example, some water purification systems are fitted with sensor TOC technology for cost savings without coordination with the end user or other technology providers. Is important to have instrumentation on a water system that can generate validated, qualified data in order to support GMP activities and important decisions. Having these conversations and choosing appropriate technology early in the process can avoid being stuck with technology that is not fit for purpose. Another aspect to consider is the longer-term relationship with various equipment vendors and providers. Ideally, it will be a true partnership that results in successful projects across facilities.

Dingle: Cooperation between all parties is critical. Too often microbiology has been an afterthought in these projects. Part of the reason is that traditional microbiology has not needed lots of consideration. For example, if using a settle plate to monitor, a surface to set the plate on is all that is needed - not a lot of planning needs to go into the design. However, today, designing a new or renovated facility offers a great opportunity to implement any of a number of rapid or alternative microbiological methods that have become more prevalent over the last few years. These methods may have requirements that will affect design and will be very difficult to implement if they are not in the plan from the beginning. This means that a good user requirement specifications (URS) document will need to created early on in the process. Since most users will have limited knowledge of these methods, extensive involvement of the equipment vendors, microbiology technology providers, and sponsors is necessary to assure success.

Peacos: Cooperation between these entities is always extremely helpful. That being said, it is important to cultivate an open, transparent and collaborative relationship with each member of your project team. As these providers are interested in assuring the success of their clients and are also usually eager to improve and expand the scope of the services they provide and their problem-solving skills, such a relationship can facilitate cooperation between the suppliers. Making them see the potential benefit for their own business is of course critical in achieving this goal. That being said, it is important to make sure you speak to the right contacts. It is also important to make sure you have someone on your internal team with the appropriate business/negotiating skills if you opt to engage in such discussions. All that being said, some entities will always be more receptive to cooperation than others, especially when it comes to proprietary knowledge and confidentiality, but if you can get them to work together, some pretty innovative solutions can result that are beneficial to all.

Over the next few years, what do you see as some of the most critical industry issues that will affect microbiology identification, detection, and removal efforts?

Wills: We expect that the industry will continue to evolve under the current pressures of developing high-profile vaccines and drugs. Along with that, we look forward to seeing the developments in the acceptance of recombinant reagents not only in the US but also globally as the recombinant reagents become more commercially available worldwide. We are very much looking forward to ongoing collection and sharing of data on endotoxin concentrations when using recombinant reagents and their potential uptake where appropriate.

Sandle: With microbial identification I think we’ll see more requirements for the use of genotypic methods. Technology that can sequence or match microbial contaminants, showing how different organisms relate to each other has always been very useful, especially when making product release or reject decisions. As this technology becomes more affordable, its use should decrease.

With detection, the adoption of spectrophotometric particle counters is slowly edging forwards. These technologies can help to differentiate inert and biologic particles and to provide some useful real-time assessments of environmental control in cleanrooms, enabling processes to be halted if there is an apparent microbial risk in an area.

With microbial removal, the battle may be easier with microbial exclusion. The latest draft of EU MPG Annex 1 has given the industry a strong nudge towards the adoption of barrier technology.

With more direct microbial removal, there’s some interesting work going on with microbial enzymes designed to remove a wide variety of contaminants from various surfaces. One method is based on the affinity of microbes for hydrocarbons that are digested, producing harmless carbon dioxide, water, and soluble fatty acids, as an alternative to solvent cleaning.

Parker: As emphasis on the biologics field increases, methods of sterilization and monitoring must adapt to the rise in demand. The shorter stability dating of biologics will challenge the industry to complete testing closer to the date of manufacturing. Rapid microbiological analyses, with greater accuracy, must be developed and accepted by regulatory bodies. As many biologics are unable to be terminally sterilized, greater emphasis will be placed on aseptic manufacturing to prevent contamination and an environmental monitoring strategy to detect contamination.

Jonathan Stewart, Manager, Quality Control, Catalent Biologics, Bloomington: The most critical issues affecting microbiology identification, detection, and removal efforts are contracted bacterial and fungal ID, Limulus Amebocyte Lysate (LAL) derived from horseshoe crabs, and supply of laboratory items in the wake of stressed global demand.

As the time-to-result demands become shorter, the key to timely investigations lies in rapid on-site identification technology. This is a core requirement of any microbiology lab and will continue to be a critical quality requirement in the future.

For decades, the bacterial endotoxin test (BET) has been heavily dependent on animal-derived biproducts and animal model tests. Moving from rabbit pyrogen testing to horseshoe crab-derived reagents was a big step but had obvious drawbacks. In the coming years, it is critical for novel drugs to move away from traditional BET methods into new synthetic pathways proven to provide equivalent reliable results.

Global supply and demand for products essential to laboratory testing is another concern. Current demand for essential personal protective equipment (PPE) such as masks is exceeding the burst capacity of many manufacturers resulting in a drop in supply. Redundant suppliers and appropriate reorder points should mitigate testing delays, enabling the provided test results to help maintain the supply of safe and effective drugs to patients.

Hoffmeister: A critical topic will be pharmacopoeia harmonization. Pharmacopoeia harmonization or “convergence” provides better support for global regulatory agencies and addresses the global nature of bio/pharmaceutical manufacturing and supply, which ultimately benefits global patients who rely on these medicines to extend and improve their lives. The sheer number of pharmacopoeias and the current lack of broad harmonization add complexity to a company’s processes for compendial monitoring and compliance. Any level of harmonization is beneficial and moves in the right direction to help provide medicines with consistent quality to patients around the world. As the pharmacopeia start to differentiate their chapters it can cause a headache for pharmaceutical organizations to ensure compliance and harmonization of their processes globally.

Duncan Barlow, Technology & Marketing Development Specialist, Microbial Solutions, Charles River Laboratories: Over the last few years there have been increased cases of product recalls due to contamination by fungi. Very few product recalls related to fungal contamination have had a species level identification associated with them. There are many examples of fungal species associated with risk of infection to patients (e.g., Aspergillus fumigatus is a common organism that can cause serious infections in immunocompromised patients). With the increased focus from regulators on understanding to species level what organisms are found in production environments it will become more important to be able to accurately identify fungal contaminants. The advantages of this knowledge are clear: trending of isolates is required and fully understanding what species you have present will allow for accurate risk assessment and proactive remedial action. It will also aide in getting to root cause in the event of product contamination and ultimately ensure patient safety. In the past, fungi may only have been reported as “black” or “green” mold. As an industry, we need to do better than that! With recent advances in technology such as MALDI-TOF, but more importantly the reference libraries, there’s no excuses anymore for lack of species level identifications for fungal isolates.

Clow: There is increased attention on detection and identification of Burkholderia cepacia in the industry. When a presumptive positive is obtained, two common identification methods, MALDI Biotyper testing and 16S Gene Sequencing, have limitations in identifying or ruling out B. cepacia. The 16S Gene Sequencing identifies the Burkholderia cepacia complex, which currently includes 21 different species. This may not be specific enough in some situations. The Burkholderia cepacia complexcan only be fully identified by performing Multilocus Sequencing Typing (MLST) which can be expensive. As more compendial guidance is provided related to testing for the presence of B. cepacia, the industry must address and balance the identification limitations with testing requirements, contamination risks, and remediation measures.

Moldenhauer:

  • Microbial detection will increasingly go to chemistry-based methodologies, e.g., MALDI-TOF. Microbiologists do not typically understand these types of systems. As such, there will either be chemists in the microbiology laboratory and/or the microbiologists will need to learn about the key parameters for the chemistry-based methods they are using.
  • Companies need to come to realize that rapid and alternative methods are a reality. Regulators are accepting of these methods. This should remove some of the fear associated with the use of these technologies. Many of these newer methods are superior to the detection methods that are currently available.
  • Eliminating microbial contamination will go forward in a couple of different directions. First, we should be looking at products that “prevent” contamination rather than responding after it is already contaminated. There are many products available that prevent contamination, e.g., antibacterial paints, antifungal building materials, mold preventative agents, and the like.

In addition to consideration of “preventing contamination”, we need to look at the newer types of sanitizers and disinfecting agents available. There are several water-based technologies available, e.g., ozonated water (has an extra oxygen) and autoionized water (that has extra hydronium ions with a positive charge). Both of these types of products are superior in that in addition to being effective against vegetative cells, they are effective against spores, fungi, and viruses. Many are effective against coronaviruses as well. Another benefit of these newer types of disinfectants include the fact that the products are non-corrosive. Many traditional disinfectants and sanitizers that are chemically-based can cause damage to steel surfaces, and the damage can provide more opportunities for biofilm formation.

Barnarhall, Trivedi, Cannon: Microbial contamination remains a significant risk in the production of pharmaceutical products. Some of the issues the industry will have to tackle are:

  • New and innovative therapies from the industry will continue to put pressure on their teams to minimize this risk, as existing detection methods do not provide information fast enough to act on. Pursuing and adopting RMM’s and other alternative methods of monitoring water systems, raw materials and final products will prove essential to mitigating such microbial risk.
  • RMM’s provide the opportunity for real-time data collection and process analysis, which is certainly part of the increased use of analytics and data integrity.
  • Gaining acceptance of RMMs as a validated method by collaboratively working with vendors, stakeholders and regulatory bodies, to replace plate counts as processes require faster and faster turnaround time for results.
  • Defining overall control strategies for adoption across their facilities, to minimize risk and implement lean quality principles. This will necessitate adoption of RMMs to achieve overall process control.

Cundell: After making huge advances in clinical microbiology as a first-line identification method, the potential of MALDI-TOF mass spectrometry for microbial identification in the pharmaceutical industry is finally being realized, especially in support of environmental and water monitoring. Given the high capital cost of the instrumentation, contract microbiological testing laboratories have been highly successful in offering this service especially when supported by 23S and 16S rRNA base sequencing. For pharmaceutical QC labs, with a high volume of microbial identifications annually, the low cost per identification and the short time to a result makes the return on investment very favorable.

An emerging technology that is being evaluated by the pharmaceutical industry is Raman spectrometry that has the potential to combine microbial enumeration with single cell identification. With a technology that provides unique intensity-wavelength spectra for different microorganisms there will be serious database limitations initially and any microorganisms identified to genus or species must be evaluated for their objectionableness, if recovered from non-sterile pharmaceutical products. A challenge will be evaluating the potential impact of a wider range of isolators. I believe that the approaches found in the 2014 PDA Technical Report No. 67 Exclusion of Objectionable Microorganisms from Non-sterile Pharmaceutical and OTC Drug Products, Medical Devices and Cosmetics are still applicable.

Our response to objectionable microorganisms could be more nuanced. The impact of human pathogens depends on the genus, species, strain type, antibiotic resistance profile, route of administration. And the infectious dose. With modern molecular technologies, including repPCR, multi-locus sequence typing, and whole genomic sequencing, we may be better positioned to determine the pathogenicity of microorganism isolated from a pharmaceutical product.

Miller: The ability to have a champion at the manufacturing site who will be the sole point of control for the implementation of next generation microbiology methods, as well as a commitment from the senior leadership team to support these types of programs.

The future of medicine will include personalized treatments, such as gene and cell therapies, that require the industry to think out of the box in terms of contamination control, in-process microbiology competences and the release of finished product much faster than conventional pharmaceuticals.

Jones: As with many sectors of the pharmaceutical industry the implementation of automation and robotics will have a significant effect on the quality of the microbial data. Minimizing the involvement of the human in the process will reduce the possibility of false positive test results due to having more people in the clean areas or sampling or test issues. Starting points have been with the installation of steam in place sampling systems for a range of collection bags/bottles to reduce the introduction of organisms either to the fermenter or to the collected sample. These units could facilitate the use of robots as sample collection devices that perform the EM testing and transport the test samples to another robot that performs the analytical test. After testing, the result, the meta data around the sample and the test equipment can be fed back into the databases that are being designed as part of the digitization of the manufacturing 4.0. Times, they are a-changin!

Kazemi: I see accurate rapid microbial test methods instead of traditional microbiological methods as one of the most critical industry issues. It allows for a faster time to results, enabling companies to release raw materials quickly, transfer in-process work to the next stage, and bring finished products to market. This shortens the production cycle, reduces inventory requirements, and frees up working capital.

Neumeyer and Wadsworth: Leveraging Process Analytical Technology is increasingly important in environmental monitoring programs. Traditional sampling methods and laboratory analysis are just not sufficient for the demand for safe and effective medicines. When looking for more efficient and quality methodology, look for ways to deploy process analytical technology. For analytical methods that continue to require laboratory-based testing, it will be critical to deploy techniques and technologies that improve efficiency. Particularly in the endotoxin detection market, efficiency gains are highly desired, but it is important to achieve efficiency in a sustainable fashion. By leveraging automated technology that relies less on natural resources, laboratories can implement solutions that have positive impacts on personnel, business goals, and the environment.

Dingle: The continued progression toward new technologies and test methods is one of the biggest issues that will affect the industry in the coming years. Regulatory agencies have been pushing for this change for some time, but lack of clear direction on how this can be done has severely hampered implementation due to fears of how they may be received by inspectors. While many liked the idea of making changes, and could see advantages in doing so, most were averse to the risk because the old ways were viewed as “good enough” and did not require an extensive effort to defend.

The industry is changing though, and there are a number of situations where the old ways may no longer be “good enough”. For example, if a product must be administered within days, waiting two weeks for a sterility test result is an obvious issue. This is one of the reasons why rapid sterility testing is one of the areas where the most progress has been made with more detailed guidance documents being generated. However, changes like switching from batch to continuous manufacturing and the surge in cell and gene therapies have necessitated the use of new technologies like gloveless isolators and real-time continuous viable particle counters where clear guidance still does not exist. Fortunately, a clearer path to implementation is starting to emerge as interactions between users, regulators and instrument vendors are shedding light on validation and implementation expectations.

Peacos: I think emerging pathogens will become a larger issue. As identification techniques improve, we are finding that some organisms previously thought to be generally innocuous may actually be more virulent, more resistant or otherwise more problematic than previously thought. There have also been studies published recently suggesting that some organisms may have been incorrectly identified or classified in the past. This combined with the rise of antibiotic resistance in general makes me think that we are going to see more challenges like the Burkhoderia cepacia complex in the near future, which required the industry to rapidly develop the specific detection method now required by USP<60>.

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