Microbiology Roundtable

• Jessica Rayser - Charles River Laboratories, Senior Product Manager - Accugenix
• Tony Cundell, PhD - Microbiological Consulting, LLC - Scarsdale, NY
• Janet Yancey-Wrona - Senior Marketing Manager, Testing Solutions - Lonza
• Jeanne Moldenhauer - Excellent Pharma Consulting
• Frank Panofen - Director and GM Life Sciences - Particle Measuring Systems
• Donald Singer - Senior Microbiology Technical Consultant, North America - Ecolab Life Sciences
• Sydney Jannetta - Product Application Specialist - SUEZ – Water Technologies & Solutions
• Anne Connors - Senior Field Marketing Manager, BioMonitoring - MilliporeSigma
• Luis Jimenez, PhD - Professor of Microbiology, Department of Biology and Horticulture - Bergen Community College
• Tim Sandle, PhD - Head of Microbiology and Sterility Assurance - Bio Products Laboratory Limited
• Robert Westney, M.S. QA/RA, RAC, CMQ/0E - Founder and President, Cryologics, Inc - Principal Consultant, Westney & Associates Consulting, LLC
• Mike Dingle - Senior TSI Application Specialist

In general, over the last year, what are some general industry trends that have resulted in more emphasis being placed on microbiology tools and technologies?

Jessica Rayser, Charles River Laboratories, Senior Product Manager, Accugenix: Besides the obvious answer of COVID-19 vaccine production, availability, and safety, we continue to see pharmaceutical companies respond to new and stricter regulatory requirements like Annex 1 and USP <60>. We’re seeing an increase in the frequency of cleanroom validations, environmental monitoring, microbial testing and identifications, and trending of data.

Tony Cundell, Ph. D., Microbiological Consulting, LLC, Scarsdale, NY: The biggest driver for change in the area of pharmaceutical microbiology continues to be the industry reaction to the planned revision of the EU Good Manufacturing Practices, Annex 1 Manufacture of Sterile Medicinal Products, especially the requirement that a Contamination Control Strategy (CCS) should be written and implemented across our facilities in order to define all critical control points and assess the effectiveness of all the controls (design, procedural, technical and organizational) and monitoring measures employed to manage risks associated with contamination. CCS implementation encourages companies to undertake a comprehensive and systematic review of their manufacturing practices. The expectation is that sterile product manufacturing facilities should be designed and operated to exclude operators from critical aseptic processing operations. As a microbiologist who has worked long and hard, over the past 20 years, for the implementation of modern microbiological methods, like my colleague and friend Dr. Michael Miller, I was encouraged by the statement, as a footnote below Table 7: Maximum action limits for viable particle contamination, that if different or new technologies are used that present results in a manner different from the colony-forming unit (CFU), the manufacturer should scientifically justify the limits applied and where possible correlate them to CFU. We need to recognize the limitations of our current growth-based microbial test methods in terms of their inability to detect and enumerate the widest diversity and highest count of microorganisms, low sampling frequencies, and protracted incubation times. Technologies like bio-fluorescent particle monitoring are far superior to these technologies for in-process monitoring of our facilities, utilities, and product intermediates. Let’s find a pathway to implement these technologies. 

Another trend that I support is the formation of ad hoc industry groups, standard-setting organization, and government divisions like the PEMM/BioPhorum Bio-Fluorescent Particle Counting Group, Kilmer Collaboration, USP Microbiology Expert Committee, PDA RMM Task Force and National Institute of Standards and Technology RMTM Consortium, all actively promoting modern microbiological methods.

Janet Yancey-Wrona, Senior Marketing Manager, Testing Solutions, Lonza: The drivers for an increased focus on microbiology tools and technologies existed previously but are now more important and impactful than ever. A consistent spotlight on the efficiencies of the QC lab have led to increased pressure to reduce error, avoid repetitive strain injury, and streamline training processes.

Also in this time, sustainability and supply chain risk mitigation have become more prevalent in the industry with newer methods for bacterial endotoxin testing supported by the introduction of European Pharmacopeia chapter 2.6.32 Test for Bacterial Endotoxins using Recombinant Factor C (rFC), along with recent FDA-approvals of drugs and medical devices released with the rFC endotoxin detection method.

We’ve also seen developments in the global harmonization and integration of software solutions, procedures, and purchasing processes, especially within larger pharma/biopharma customers. Discussion has progressed into implementation, and with that comes new challenges of aligning user requirements and specifications across cultures and continents.

As complexity of product and in-process matrices increases with new technologies, we also see a higher demand for versatile QC testing systems able to offer multiple method options on one platform, such as the Lonza PyroTec® PRO System that supports both Kinetic-LAL and rFC methods for bacterial endotoxin testing.

Jeanne Moldenhauer, Excellent Pharma Consulting: The increased focus on the human microbiome has resulted in several new technologies that are available for microbiological testing, especially in the area of identification of microorganisms. The other technologies developed are a result of the COVID-19 pandemic and are in the area of decontamination and contamination detection.

Frank Panofen, Director and GM Life Sciences, Particle Measuring Systems: Microbiology is an area which has been very conservative historically. For the past five years, the industry has struggled to identify technologies and the return on investment for single solutions. Only organizations with a strong, focused approach across the entire application range really find good payback. These ROI scenarios enable technologies to evolve and their manufacturers to identify key areas of benefit. As a result, automation and real time testing have become the key innovation area.

Donald Singer, Ecolab Life Sciences, Senior Microbiology Technical Consultant, North America: Two trends that stand out are from the fields of cell therapy and vaccines. The use of PCR (polymerase chain reaction) for rapid detection tests during the pandemic has led to more interest in the use of PCR for detection of microbiological contaminants such as mycoplasma testing or for a sterility-type test. As cell therapy grows towards more commercialization, there are more new technologies being developed to close (formerly manual) process steps, and isolator usage has begun to increase for cell line manipulations to reduce human exposure. Contamination control and patient access (rapid turnaround time) is of utmost importance in current cell and gene therapy, thus microbiology tools and technologies have become a key part of the strategy. 

In addition to these, the ongoing revision saga for Annex 1 has set a norm for the importance of microbiology (and it’s tools and technologies) in many different aspects of sterile manufacturing, which includes having a contamination control strategy (that is monitored), showing evidence of facility disinfection effectiveness, and the use of rapid microbial testing. 

Sydney Jannetta, Product Application Specialist, SUEZ – Water Technologies & Solutions: The rigorous demands the industry experienced this past year to research, test, and move product in urgent timeframes has demonstrated the need for simplification in the QC microbiology lab. Pharmaceutical and biopharmaceutical companies are looking for ways to streamline production, improve operational efficiency, and increase overall throughput. The need for innovation, especially in the area of rapid micro methods, and the need for improved tools and technologies, has never been higher. Consequently, the demand on instrument and consumable manufacturers to develop novel solutions quickly has also increased. Some manufacturers have risen to these challenges by introducing newer microbiology tools that leverage microfluidics, robotics, and/or updated software to improve efficiency. The goal of these technologies is to decrease the time needed for training and validation, increase uptime and throughput, and maintain compliance.

Anne Connors, Senior Field Marketing Manager, BioMonitoring, MilliporeSigma: It seems that more pharmaceutical manufacturers are identifying technologies that are easier to implement and not overly complicated to validate and install. Rapid methods, automation, data integrity continue to be forefront themes in discussions within the industry.

Luis Jimenez, Ph.D., Professor of Microbiology, Department of Biology and Horticulture, Bergen Community College: When it comes to microbiology tools and technologies, last year’s worldwide situation due to the COVID-19 pandemic has triggered an enormous amount of research and development to minimize the impact of SARS-CoV-2 on human populations and the world economy. The rapid sequencing of the original strain by Chinese microbiologists and the widespread dissemination of the data to scientists all over the world provided the foundation to develop rapid detection technologies and the current vaccines. The genome sequencing also provided a starting point to determine the genetic characterization of the virus and analysis of the different genes and their functionality. Basic understanding of gene function and COVID-19 pathogenesis will lead to the development of new drugs to inhibit some of the life stages of SARS-CoV-2 allowing the treatment of patients after infection while vaccine development and optimization responding to the inevitable emergence of variants will protect susceptible populations against viral infection. Because vaccines are sterile products, manufacturing of the messenger RNA (mRNA) vaccines required intense product and manufacturing development along with the validation of the different steps during manufacturing to support stability, safety, and efficacy. These validations comprised environmental monitoring of different manufacturing processes during production along with endotoxin and sterility testing of raw materials, bulk, and finished products. 

Tim Sandle, PhD, Head of Microbiology and Sterility Assurance, Bio Products Laboratory Limited: The importance is seen with both inspection trends (in both the U.S. and Europe), where microbial contamination and sterility assurance issues continue to rate high. A similar trend is seen with recall data, where confirmed or suspected microbial contamination continues to stand as one of the top three reasons for recall.

This leads to consideration as to why these issues happen. Where batch release is performed, how is microbial contamination missed? Is this a lack of knowledge or appreciation of risk? Or is it due to inadequate testing? Or perhaps a lack of controls, geared around protecting products and process from contamination. This itself is a quality by design matter, as well as an understanding of what an item of equipment does, how this is assessed and how to connect processing parameters back to the original validation.

Robert Westney, Founder and President, Cryologics, Inc., Principal Consultant, Westney & Associates Consulting, LLC: In general, in my personal experience, I haven’t experienced recent general industry trends that have resulted in overtly more emphasis being placed on microbiology tools and technologies. My industry colleagues may disagree. I have very much respected and admired the great long-time efforts of those who champion rapid microbiology methods (RMM), particularly Dr. Michael Miller. His approaches to justifying RMM I think have always been compelling and sound. Microbiology technology, I think, is a slow-moving train in our industry. My colleagues on USP’s Expert Microbiology Committee have done an excellent job with putting forth USP <60> regarding Burkholderia cepacia Complex, helping to address the current regulatory scrutiny in this area. This is one of the “tools”, albeit a classically culture-based reference. And certainly, advances in automated endotoxin testing (even some sterility RMM) have become standard fare accepted by regulatory authorities for the past several years.

Specifically, how has the COVID-19 pandemic affected pharmaceutical companies in terms of their microbiology containment and control efforts?

Rayser: COVID-19 forced manufacturers to take a closer look at their traditional microbiology testing methods and procedures. We’ve seen many more companies willing to adopt rapid methods to meet increased production needs. Also, the materials and plastics supply shortages drove flexibility and change. It’s also interesting to note that companies’ COVID-19 cleanliness and sanitation measures also resulted in less contamination events in facilities.

Cundell: As a member of the PDA COVID-19 Task Force, I co-authored the much read review article published as Cundell, A.M., D. Guilfoyle, T. R. Kreil and A. Sawant Controls To Minimize Disruption of the Pharmaceutical Supply Chain during the Covid-19 Pandemic PDA J. Pharm. Sci. & Technol. May 2020. The authors concluded the unavailability of healthy essential workers in manufacturing, facility maintenance, QC testing, and warehousing, the discontinued supply of critical materials such as pharmaceutical ingredients, personnel protection equipment, solvents, filters, and packaging materials, and a lack of a functioning distribution system had a more serious potential for disruption to the pharmaceutical supply chain than the very low potential for SARS CoV-2 contamination of our products. Lipid-enveloped RNA respiratory viruses like SARS CoV-2 do not persist outside the human body, are readily destroyed by EPA- registered disinfectants, and would be excluded from pharmaceutical manufacturing areas by our HVAC systems.

Wrona: We have seen growing interest in the automation of bacterial endotoxin testing among vaccine manufacturers and CDMOs needing to rapidly increase their output while also dealing with a reduced work force due to COVID-induced constraints and generalized labor shortages. Further, there has been increased focus on remote access with data integrity. With reduced staff available onsite, remote access to data and reports has become a priority, while also maintaining data integrity requirements.

Moldenhauer: In most companies, there were additional procedures established for contamination control.

Panofen: The microbiological departments are the litmus test for competence in hygienic behavior and disinfection inside these facilities. Suddenly being asked to support hygiene programs for full site operation created great distraction, stress and above and beyond time commitments in these departments.

Singer: Containment has always been a method of microbiological control, yet the pandemic increased the visibility and understanding of how robust engineering controls, such as well-maintained containment and HVAC systems, can be effective in keeping adventitious contaminants out of critical areas. Many companies didn’t have to change their process design and controls if operators followed procedures of good health, good hygienic practices, and maintained proper gowning practices. Some companies added additional hand sanitization procedures and health restrictions for entry into contained areas, such as cleanrooms, to emphasize the concern over seemingly ‘minor’ symptoms potentially being higher risk.

Connors: We have seen an uptick in need for training, which was mostly carried out remotely during most of the pandemic. There seemed to be the biggest focus on environmental monitoring, and pyrogen testing in the past year. 

Sandle: COVID-19 has affected matters is terms of staffing, which can have an impact on contamination control. As far as the risk to the virus is concerned, the coronavirus is an enveloped virus which means for biologics, where viral inactivation steps are required, the virus is straightforward to kill by disinfection or heat; to inactivate through pH adjustment, or to remove through nanofiltration. It does not present a particular risk compared with other viruses of concern.

Westney: The biggest impact that I have seen from the COVID 19 pandemic is, simply enough, PPE and laboratory supply chain issues. These are critical aspects of microbiology testing, and contamination containment and control efforts. Manufacturing and QC Microbiology colleagues with whom I have corresponded have overwhelmingly reported that supply issues with these materials (such as sterile disposable gloves, disinfectants, micropipet tips, microbiological media, etc.) have often hindered manufacturing and laboratory operations. For larger companies, their ordering volumes afford them leveraging abilities to be first in line for backorders. For midsize or smaller companies, this challenge lingers, to the point of hampering deliverables. While it seemed that post-pandemic supply issues were beginning to ease a few months ago, the COVID 19 Delta variant surgency appears to be a threatening force in this area again.

Mike Dingle, Senior TSI Application Specialist: The pandemic has become the latest of many forces pushing the industry away from traditional, labor-intensive, culture-based microbiology, and towards the adoption of alternative methods that automate testing and data collection. Advantages like testing that does not require multiple technicians in the lab counting plates or easy access to data became necessities when social distancing rules and work-from-home initiatives were put in place. This has led to a wider realization of the other benefits that alternative methods offer, and may have been the final push needed for more widespread adoption.

As microbiology detection and control efforts become more comprehensive, detailed, and labor intensive, what are some strategies pharmaceutical companies can implement to remain in compliance?

Rayser: Pharmaceutical companies need to be open to new ideas and learn about up-and-coming technologies. The aim of many rapid micro methods is not just to be faster, but to be easier for the user as well. Both suppliers, end-users, and regulators have begun to collaborate more and more, simplifying the implementation and validation process to increase adoption while still maintaining a high degree of control and demonstration of performance. They should continue to do so to preserve this momentum and spirit of innovation. I also think there needs to be continued investment in contamination control and thorough investigations, from the very top of the organization - all the way down.

Cundell: The widespread use of restricted access barrier and isolator systems, single-use processing equipment, computerization, and automation will advance our microbiology detection and control efforts, and actually will be less labor intensive not more. 

This was brought home to me over a decade ago when I had the opportunity to tour a new regional dairy factory in New Zealand that replaced a number of local dairy factories manufacturing milk powder and casein. When I commented on the small number of employees in the factory and the high degree of automation, the plant manager emphasized for New Zealand to be competitive in the global market, the operation had to be productive, flexible, and cost effective. The same should be true in the pharmaceutical industry. 

The widespread application of modern quality concepts like quality by design, process analytical technology, and quality risk management will enhance not diminish our level of compliance.

Wrona: Global harmonization allows companies to maintain compliance, while simplifying their workload. To achieve this, the software and data analysis systems must be suitable for global implementation. 

In addition, the drive towards paperless labs continues reducing the potential for errors and allowing companies to remain in compliance with a global, harmonized approach that minimizes site-specific variation and change requirements.

Moldenhauer: Not all of the new detection and control procedures are more labor intensive. Many of them have been simplified in their use and time to detection. It is important for companies to carefully evaluate the new control systems prior to implementation to understand the true costs of time and resources. These costs should be considered as part of a risk assessment to achieve the desired benefits. 

Panofen: My answer is straightforward:

• Automate what can be automated and focus staff on the critical data generation steps.
• Use scientific approaches to decide for the technologies and methodologies used.
• Apply QRM methods to decide how data is handled and transferred into practice.

Singer: The most significant strategy for showing compliant behavior and being scientifically diligent is to generate and utilize relevant and timely data. Evaluating the need for types of data that can indicate excursions from acceptable microbiological quality (e.g., for environmental monitoring or bioburden) can lead to more efficient sampling plans and timely assessments of results. The use of automated instrumentation, improvements in microbiological testing, and digital data management bring efficiencies to the microbiologist that enhance their ability to stay in touch with the operational controls they oversee. A modern pharmaceutical microbiology supervisor should always be seeking ways to reduce labor-intensive sampling and testing while maintaining good oversight of manufacturing controls and materials quality. Time saved in the laboratory will lead to more time to be ‘microbiologically’ attentive to the manufacturing operation and its infrastructure.

Jannetta: One action pharmaceutical companies can take to remain in compliance is to use instrumentation and software that are fully compendial and defendable. Working directly with instrument manufacturers can ease concerns around compliance, while also potentially reducing the amount of labor required for compliant system setup and routine analysis. Instrument manufacturers should be knowledgeable about 21 CFR Part 11 compliance, Pharma 4.0 framework, and data integrity guidelines that include ALCOA+ principles. Partnering with suppliers who have deep expertise in these areas is highly recommended and should be an important aspect of the overall compliance strategy. 

Connors: One strategy that could be implemented would be to leverage existing expertise and vendor validation documentation quickly. 

Sandle: It is good practice to periodically assess the value of samples. What is the objective of the sample? What does the result tell me? This is something that can be approached through risk assessment. This fits in with risk based monitoring, where the focus should be with achieving control, using as many real-time measurements as possible, and monitoring in higher risk or more variable areas, such as where personnel need to interact with exposed product. 

In addition, automation and the application of rapid microbiological methods can help. Caution is needed if the goal is not increasing labor, as some rapid methods take just as long (or longer) to prepare, but it is the time to result that is quicker.

Perhaps the optimal methods are those that decrease the time spend with sampling handling, processing or reading. In many laboratories it is the plate counting that takes the greatest amount of time. Therefore, the technologies that either read plates are particularly useful, as are rapid methods that can direct testing away from culture-techniques. 

Westney: In three words: staffing, equipment and space. This is “old school” stuff that remains to this day, despite the efforts described in the question. I’ve experienced this for several decades. It’s a common anecdote that QC Microbiology is too often an afterthought when

it comes to addressing the challenges of our evolving industry with regard to cGMP (with the “c” being “current”, as we all know). For example, I am currently assisting a client who has had an (expensive) isolator lying idle for a year. Why? Because they don’t have the personnel, resources, financial support, or space to validate it. This would be an invaluable asset that, if/when implemented, would help the QC Microbiology laboratory meet cGMP’s, and therefore company goals. I understand that all too often, as folks move up the “food chain”, that Microbiologists are usually not a part of Quality Control senior management, and therefore don’t understand the unique challenges and needs of QC Microbiologists to do their jobs and support the firm. Such management needs to embrace and support the goals of their QC Microbiology team.

As the pharmaceutical industry is a global business, what advice can you give companies that operate in multiple worldwide locations in terms of complying with different microbiological regulations and different compliance organizations?

Rayser: Partnering with a reputable, global company for microbiological testing needs can be a huge advantage. It allows a company to harmonize their QC Micro programs across sites, ensuring the same level of quality and compliance globally. Supplier and change management becomes easier, quality is increased, supply chain is more stable, and usually pricing is better!

Cundell: It is a challenge to satisfy the unique requirements of different national boards of health that insists on a microbial specification that does not make sense for a product and is not requested by other regulatory agencies. It almost appears as a challenge to their authority, if you advance a technical justification for not wanting to comply. Tests for the absence of specified microorganisms and antimicrobial preservative effectiveness and marketed product stability test parameters are often involved in these outliers. For example, advising that we decline to sell a product in a major market because their board of health wants the preservative concentration reduced to 80% of the label claim does not sit well with our sales and marketing colleagues.

In area of GMP compliance, we are seeing a convergence of expectations, promoted by growing global membership in the PIC/S organization and the European leadership in sterile product manufacturing as a result of the revision to the EU GMP Annex 1.

Wrona: Specifically for bacterial endotoxin testing, opinions about the use of recombinant endotoxin testing reagents for sustainability and the adoption of rFC as a compendial method in the European Pharmacopeia have made for exciting discussions with key stakeholders internally, and with customers and peers in the relevant industry workgroups. Along with automation, sustainable endotoxin testing will once again be a major focus of our 6th Global Endotoxin Testing Summit, a virtual seminar series taking place in September. The current lack of global harmonization around the adoption of rFC into the different global pharmacopeias presents unique challenges for the companies that seek to harmonize their testing systems. Our advice would be to look at the science and the regulations, understand the differences between various test methodologies, and let the data drive decision-making.

Moldenhauer: It is important to be “in the know” of what is going on in different compliance agencies. If you don’t have the resources at your company, it is important to be involved in organizations that maintain this information. For example, the European Compliance Agency (ECA) keeps detailed records of what compliance requirements are in place and when they change. This organization provides the members with digital access to all of these requirements, as well as a newsletter with updates.

Panofen: Science and process understanding are the guiding principles for all operations today, and they have become synonymous globally. By following this higher standard, companies can facilitate worldwide compliance to be consistently and successfully applied anywhere where they do business. Pharma can no longer blindly follow regulation without giving up leadership and credibility.

Singer: Microbiological compliance is built into regulations, often in subtle and general terms, yet sometimes prescriptive. A global company should be aware and knowledgeable of all relevant regulations, plus pharmacopeial guidance, in their marketing regions. Regulations from EMA (Europe), FDA (United States), WHO (Asia) and TGA (Australia) have strong regional influence, and the PICS (Pharmacopeial Inspection Cooperation Scheme) documents have become a global source of mutually agreed guidance between the global regulatory agencies who participate. The United States Pharmacopeia, European Pharmacopeia and Japanese Pharmacopeia also influence microbiological practices, while numerous other countries that have their own pharmacopeias may be more explicit in specific items. Agencies in different parts of the world are aware of the changing regulations from their counterparts, so it is diligent to have this broad view of the regulations, especially if one agency makes revisions sooner than another. Companies should also be aware that regulations can also have a cultural perspective that will influence pharmaceutical manufacturing and GMPs in a particular region.

Jannetta: Companies that have a global presence are required to know and understand varying regulations across the world. The same is true with instrument and consumable manufacturers. Working with a supplier that also has a global footprint makes for a great partnership; suppliers gain knowledge from their global partnerships and service to the industry and can be a useful resource when global businesses need to maintain compliance across multiple facilities. Companies also want to be sure their vendors understand the need to keep all regions connected and that the vendors are using technology developed and manufactured for enterprise implementation. Ensuring technology meets all global compliance requirements and harmonizing methods wherever possible will provide great benefits in the long run.

Connors: Talk to each other. Set up an internal network of resources and experts and meet at a pre-determined frequency. There should be an internal regulatory committee that reviews changes and identifies necessary changes in testing, depending on the location and regulatory impact.

Sandle: It would be good if national and supranational standards could be aligned. A few years ago there was some good work around harmonization under ICH, which brought some microbiological monographs together across the USP, EP, and JP, such as the sterility test and microbial limits test. However, this process appears to have slowed down and there are some key divergences between compendia. The case of recombinant lysate and its validated status for endotoxin testing is a case in point, between EP and USP. In other areas, USP has developed a good chapter on Burkholderia cepacia testing in the context of non-sterile products manufacturing, whereas there’s no sign of much happening in the EP space. 

Another example of divergence is with the update to the global biocontamination control standard – ISO14698. The plans to update this for a global audience faltered and instead a European Standard was produced – EN17141. So now we have two standards to address contamination. This isn’t really very helpful.

Keeping track of standards and interpreting them is a time-consuming and challenging task. We can rely on publications like American Pharmaceutical Review to help, but the pharmaceutical microbiology community needs to get together more often on a global scale and to work together so that global standards can be set – microorganisms do not respect national borders!

Dingle: Communication is key. There is always going to be some segregation due to geography, but there are a few things that can be done to facilitate easy compliance. One is to have a global quality system so that audit findings and procedures can be accessed by multiple facility locations to enable them to learn from each other. Another, and maybe the most critical, is to have frequent global microbiological meetings with your multiple facility locations. Anything that can be shared—whether it is reviewing corrective and preventative action (CAPA) plans or audit findings—evaluations of new technologies, etc. will be beneficial. However, the real value will be building a support network that can be invaluable in addressing or preventing compliance issues.

Looking ahead, do you see the COVID-19 pandemic as having a permanent impact on the industry and its microbiological compliance efforts?

Rayser: The COVID-19 pandemic really shined a spotlight on drug development and pharmaceutical production. There were several mainstream news stories about drug shortages and drug quality, and I think there will be even more public and regulatory scrutiny on contamination control strategies and risk mitigation in the future. Furthermore, just like so many other industries, supply chains and deficiencies in day-to-day operations were exposed during the height of the pandemic. However, the pharmaceutical industry is a shining example of how to adapt and rally efforts together to meet a common goal. The partnerships between so many pharma and biotechs to deliver not one, but three vaccines to the global population was amazing. Many of these companies leveraged or quickly pursued rapid technologies to help deliver these products to a global population, replacing traditional methods when speed was critical.

Cundell: The ability of our industry to deliver multiple safe and effective vaccines against the coronavirus SARS CoV-2 in less than 12 months after the RNA sequence was published is truly amazing. How did this happen? The resources, knowledge, skills and energies of dedicated professionals in vaccine development, volunteer recruitment and clinical trials, regulatory submission and review, vaccination priorities setting, cold chain operation, and vaccination delivery were fully engaged for the first 12 months. Many of these activities were conducted concurrently and not sequentially, speeding up the overall process.

Permanent industry changes due to the COVID-19 pandemic include the adoption of the modified mRNA technology for vaccine production and some cancer therapies, widespread use of remote working by pharmaceutical professionals, remote regulatory inspections, realization that accelerated vaccine development, clinical trial, regulatory approval timeline was reduced from 4 years (Mumps vaccine) to less than 1 year (COVID-19 vaccines) was possible, recognition of our reliance on foreign manufacturers to home sourcing drug substances, drug products and critical suppliers is not in our long-term interest, and an increased use of CMOs especially for bulk vaccine manufacturing and fill/finish operations.

In my March 2021 PDA Letter article The Role of Current GMPs in COVID-19 Vaccine Production, I concluded that manufacturing processes and product release testing controls will make an important and sometime overlooked contribution to the lot-to-lot consistency, safety, and efficacy of vaccines against the SARS-CoV-2 virus. Furthermore, good product and process design and control, meeting all regulatory standards, and strict adherence to Good Manufacturing Practices will make a critical contribution to vaccine safety and effectiveness. Preventing microbiological contamination is an integral part of these efforts.

Wrona: The unique challenges posed by the COVID-19 pandemic have necessitated progress across a number of key areas such as the automation of sampling, QC testing and data trending for the multiple types of QC tests. I see this progress continuing long beyond the current pandemic because such automation enables personnel to focus on high value data analyses and decision-making rather than manual, time intensive and error-prone processes. During the pandemic, systems have been adapted for global deployment and remote access, while maintaining data integrity. This approach will continue because it provides further efficiencies for the globalization of the industry and helps mitigate continuing labor shortages. 

Moldenhauer: The COVID-19 pandemic will have a long-lasting impact on microbiological control in the industry. It was a wake-up call to many, who believed that this kind of thing couldn’t happen. Many different industries have been affected by the need for contamination control and a variety of new technologies have been developed to aid in the detection, capture, and elimination of contaminants (microbial and viral).

Panofen: There is a stronger awareness in all stakeholders that hygiene, microbiology and disinfection topics have a greater influence on final quality. The microbiologist within a company has received increased reputation and influence. The most critical aspect is that microbial data management with the purpose to generate scientifically solid information and related actions has received more attention.

Singer: A couple of decades ago it was good practice to have contingency plans in place for media and reagents for microbiological testing, use of contract testing resources, and for agents for cleaning and disinfection of laboratories and manufacturing facilities. Then new procurement strategies led to getting supplies from a single source to better ‘leverage’ costs and benefits. The recent pandemic led the industry to revisit the need for secondary suppliers and contingency plans when there was a reduction, and in some cases a restriction, in supplies and resources to ensure continuity of work. This strategy has now become a rule to assure future continuity of work, including pharmaceutical manufacturing and quality testing. Every company that depended on one source of media, one source of disinfection agents, and one contract laboratory has now begun to develop a secondary supply plan. Another good outcome from the pandemic is the assurance of continuity for the need for well-trained QC microbiologists, as they were identified as essential workers in the pharmaceutical companies.

Jannetta: Yes, the COVID-19 pandemic rapidly introduced a record high demand for a new product, exposed all aspects of the supply chain, and pushed all of us outside of our comfort zone. We see this having a lasting impact on the industry. The increased and urgent demand acutely reminded us of the importance of compliance and patient safety. The pandemic has proven that the industry is capable of remarkable accomplishments, yet also has shown gaps where compliance efforts, efficiency, and innovation can be improved. Leveraging relationships and communications with instrumentation, software, consumable, and reagent manufacturers with global expertise will encourage us to stay within the tight requirements that have been outlined by regulations across all regions.

Connors: Yes, at least a long-term impact. The industry had to adapt to unforeseen supply disruptions, labor shortages and even shutdowns while remaining in compliance. Hopefully the industry will take permanent measures for risk mitigation now to prepare for any future events and seek to adopt efficient and swift decision-making protocols.

Sandle: I don’t think there will be any direct impact in terms of manufacturing, other than labor supply issues. For biologics manufacturers, good viral controls and viral inactivation steps are in place.

However, in terms of innovation, the need to produce new novel vaccines faster, then a lot of pioneering work that has been undertaken (such as with mRNA vaccines) has hopefully led to faster vaccine development times and an ability to respond to future pandemics. It is important that such knowledge is captured and shared. Since SARS, the threat posed by zoonotic infectious agents over the past 20 years points to a continuation of this level of risk and viruses of concern over the next 20 years to come. 

Westney: I personally rarely regard any impact as “permanent”. The development of, and EUA by the FDA, of the COVID vaccine was remarkable. Unfortunately, the domestic and global vaccination rate has been disappointing, particularly regional vaccination rates here in the U.S. While no one can foretell how the COVID 19 Delta variant will progress in terms of the pandemic, lack of containment and prevention via vaccination and other preventive measures may very well have the same impact, potentially greater, on supply chains as the native variant impact has had, as I described in my response to Question

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