Timothy Francis- Senior Technical Specialist, LAL Division of FUJIFILM Wako Chemicals U.S.A. Corporation; Meg Provenzano- Product Manager- Biodetection, Veolia Water Technologies & Solutions - Sievers Instruments; Vanessa Vasadi Figueroa- Executive Director of Microbiology & Sterility Assurance, Quality Executive Partners, and Owner of VVF Science, LLC.
In general, in the last year have there been any significant or interesting developments in microbiology tools and technologies?
Timothy Francis, Senior Technical Specialist for the LAL Division of FUJIFILM Wako Chemicals U.S.A. Corporation: From the viewpoint of the pharmaceutical industry clients that I work with, one of the most impressive developments I have seen is the advancements made in customized solutions for pharmaceuticals to provide specific solutions to individual needs. For example, this year has seen the development of several pharmaceutical businesses that use viral agents, such as AVV or bacteriophage, to manufacture customized drugs for unique recombinant drug products. There also has been great innovation in drug development as pharmaceutical formulations developed by computer intelligence have been undergoing development tests over the last year.
Meg Provenzano, Product Manager- Biodetection, Veolia Water Technologies & Solutions - Sievers Instruments: The publication of the revision of Annex 1 has certainly been an interesting development. The document encourages the adoption of rapid methods and continuous monitoring systems in order to minimize risks of contamination. Rapid Microbiological Methods are encouraged for Environmental Monitoring, Personnel Monitoring, and Facilities Monitoring. Annex 1 also encourages manufacturers to have a quality Contamination Control Strategy (CCS) in place in order to define all critical control points and assess the effectiveness of controls and the associated methods and frequency of monitoring. Implementing RMMs within a facility allows manufacturers to monitor any contamination much faster than traditional methods. The Annex 1 guidelines align with recent interesting developments related to RMM technologies. For example, with certain technologies for rapid bioburden testing, results can be obtained not only faster, but also with a strong correlation to culture-based methods. Adopting such a system can help users address microbial contamination in near real-time.
How has the growth of Advance Therapy Medicinal Products (ATMPs) changed the way pharma companies approach their microbiology efforts? What have you noticed?
Francis: The increase in pharmaceuticals such as Advanced Therapy Medicinal Products have created new complex needs for quality control testing that may have not been apparent for conventional pharmaceuticals. For example, pharmaceuticals made for a specific purpose that will not be manufactured in large numbers may need unique strategies for the quality control testing requirements needed for release. Regulatory bodies such as the USP have acknowledged the need for customized testing patterns for unique products manufactured in small lot numbers such as this.
Provenzano: With the industry moving toward personalized medicine, it means that Rapid Microbiological Methods (RMMs) are going to be important for ATMPs as well. Some of these therapies involve taking cells directly from the patient, administering therapy to the cells, and then returning them back into the patient’s body. It is critical that microbes are not introduced into the patient causing further illness, and speed is also important in order to avoid delays that can also impact patient safety. Implementing technologies such as RMMs and endotoxin testing systems that are fast, fully compliant, and easy to use can provide confidence to all parties involved - including the most important party, the patient.
Vanessa Vasadi-Figueroa, Executive Director of Microbiology & Sterility Assurance, Quality Executive Partners, and Owner of VVF Science, LLC: Absolutely, the growth of ATMPs has helped the field of industrial microbiology progress in gaining familiarity with shorter turnaround times and managing risk. For some organizations, this means implementing rapid microbiological methodologies, and for others it means bringing in new technology for real time process monitoring or automated release testing. The hard work with this progression is not only the test methods themselves- these have existed for 15-30 years now - but rather it’s becoming more comfortable with assessing risk, as well as understanding and managing the risks for our process and products. I see us owning risk analysis more than we have done in the past and interjecting ourselves earlier into the product development cycle. Microbiology is also more involved in facility, equipment, and process design than ever before. We have ATMPs to thank for that, as they have pushed us forward, and we are seeing ripple effects throughout other sectors in our industry such as sterile compounding and traditional aseptic processing. Preventing contamination and reducing turnaround time for its analysis makes good sense, both in the technical and business side. It’s certainly better for getting safe product out the door, especially when on the critical path for delivery to individual patients, drug shortages areas or locally compounded drugs.
Looking at regulatory and compliance issues – have there been any recent changes/updates related to microbiology operations that affect how pharma companies conduct international operations?
Francis: In my area of quality control testing for endotoxins in pharmaceuticals, the most pertinent area in which regulatory changes have been made and hopefully continue to be made is in the pharmacopeial acceptance of recombinant reagents for bacterial endotoxin testing. The development of several different recombinant reagents and their continued acceptance in end-product QC testing has led to all three of the pharmacopeial bodies to accept or formally consider these reagents. Although here in the USA recombinant LAL reagents are not compendial, It is encouraging that continued efforts are being made by the USP to provide a compendial chapter on recombinant LAL reagents.
Vasadi-Figueroa: It goes without saying that the release of Annex 1 in August 2022 has rippled throughout the industry in a way that I hadn’t seen a regulatory change do so (in a long time). Pharma companies now have a heightened sense of global responsibility with respect to contamination control, but it’s up to each company to act appropriately. While the requirement itself to prevent contamination from entering a process—and controlling its presence once detected—isn’t novel, the requirement hadn’t been mandated in such an organized and compelling manner like this latest release. What this regulatory update accomplished was to distribute the strategic control of contamination throughout every aspect of the pharmaceutical manufacturing business. As a microbiologist, I find this exhilarating and somewhat validating, but I would suppose others are a bit less thrilled. With enforcement imminent, I think companies are demanding better quality from their suppliers, asking tough questions to facility engineers, implementing better production controls, and educating the workforce on sterility assurance principles. Microbiological controls are becoming a more shared responsibility (think fewer microbiologists running around demanding action), and so all we can do now is continue to build strength on these controls and see how they are enforced by global regulators.
As the industry, and the world, slowly moves passed the pandemic, did the pandemic cause any significant changes in how companies approach their microbiology efforts? Do you see any changes in supplies, staffing, services?
Francis: After the pandemic, supply chain issues definitely created a higher reliance on the need for products, reagents, and accessories that could be reliably sources. I believe that pharmaceutical companies have begun to prioritize solutions that are resilient to global and local disruptions. In my industry specifically, I think this has given rise to a greater valuing of in-house testing. Overall, a positive aspect is a greater redundancy in in-house production. However, a negative of this new approach is that many global connections that existed before the pandemic need to be rebuilt. In-person business seems to have decreased but is definitely increasing.
Vasadi-Figueroa: I would like to think that the pandemic brought visibility to the science of microbiology and an awareness to microbes in the world all around us. For some, this meant implementing better hand sanitization practices and cleaning methods to stay safe, but for others, it meant intellectually distancing themselves from the science of it all to stay sane (which meant differently safe). Then there are the people in between, following the rules and doing their best, one day at time. These polarizing mentalities most definitely impacted our industry because people are the very fabric of our workforce. Whether they are from small, hardworking cities in American to large, bustling metropolises in Asia, people bring with them a newfound perception towards these tiny things called microbes. The diligence with respect to masking and gloving has been eroded, so even seasoned staffing have varying degrees of interest in doing it properly. New hires also find it challenging to adhere to stringent cleanroom controls, but the potential for contamination is still very real in the production environment. This translates to difficulties finding adequate staffing, or it may mean that companies are experiencing high turnover rates for persons working in the manufacturing or laboratory areas. This has only compounded the staffing complexities experienced prior to the pandemic.
Finally, what long-term changes has the pandemic left on the industry in general and microbiology specifically?
Francis: In general, the world of pharmaceuticals seems more greatly disconnected than previously. This could be a combination of the lack in regulatory harmonization with the new recombinant reagents, as well as the rebuilding of the global business post pandemic. However, a great positive that has resulted has been many specific innovations in both drug development, manufacture, and testing. For example, with the increase in reagent options as well as newer innovative instruments and manufacturing technology, the pharmaceutical world has increased in its innovative power. A specific push to this innovation was definitely the role the pharmaceutical industry played in the fight to end the pandemic.
Provenzano: The pandemic created opportunities for people to work remotely, including some QA and QC personnel. In these cases, remote data sign off is important along with electronic signatures. Manufacturers need software that allows for data to be signed at times from a home office, thus resulting in faster product release. In the case of endotoxin testing, for example, the Sievers Eclipse allows for a client/ server installation so the reviewer can sign off on endotoxin results of up to 21 samples from the comfort of their home. The pandemic also encouraged manufacturers to find and utilize other digital solutions, so many companies are joining the digital revolution and evaluating and/or implementing technologies faster than the adoption seen in the past.
Vasadi-Figueroa: There is something about the pandemic that enabled our industry to to let go of our rigid ways of the past and embrace a more flexible way of working. I don’t intend that to mean working remotely, although in some cases, it’s still quite feasible. What I intend to convey is that we must incorporate new ways of working or being more agile in the pharma workplace. We can achieve this by building resilience in our workforce by training, educating, and organizing work in a manner that keeps people truly engaged. Gone are the days where you show up to work and do one thing, rinse and repeat each day of the week. Employees expect to learn new skills, contribute to a team in a meaningful way, and do different things over the course of their tenure. For example, if you start in the Micro lab as an EM analyst, that’s great (we all started this way) but folks expect to migrate to other parts of the lab. Rather than waiting for a performance plan, companies need to rotate people from the start of their work plan by teaching them new skills and new ways of thinking critically. This builds resilience within the analyst, but also for the laboratory and greater company goals.
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