What are some of the latest RMM technologies being developed to assist pharmaceutical companies?
A few companies have developed rapid methods for monitoring pharmaceutical grade water and are currently being evaluated by early adopters or beta test sites within the industry. The technology is based on real-time detection and enumeration of microorganisms via intrinsic fluorescence when a laser (at a specific wavelength) excites cellular components such as riboflavin and NADH. Monitoring may be performed on a single water sample or in a continuous fashion when the system is attached to a water distribution system or loop. The latter would employ diverting water offof the loop and introducing a sample into the instrumentation (i.e., monitoring via an on-line connection). Although the current systems apply to water, I have a more ambitious long-term goal for employing this type of scientific principle to support the continuous monitoring of product streams in an aseptic processing operation. Here, continuous monitoring of product moving from a compounding tank into a filling machine could eliminate the need for finished product sterility testing and support the parametric release of aseptically filled product. Of course, additional controls must be considered to minimize potential contamination including the use of advanced aseptic processing environments such as isolators, closed-RABS systems and/or robotics. Additionally, significant method suitability work would need to be performed to demonstrate the formulation under test would not contribute to either false positive or false negative signals.
Another technology that has the potential for close to real-time detection, enumeration and identification of microorganisms is based on Raman spectroscopy coupled with viability staining. The method employs capturing microorganisms from an airborne or filterable sample onto a special membrane, staining the organisms with a viability substrate and then performing Raman spectroscopy only on those particles that are determined to be viable from the staining process. The Raman spectral signature would then be compared with a library of known microorganisms. This method eliminates the potential for false positive responses from non-viable cells when using Raman spectroscopy alone.
Additionally, a number of firms are developing the next generation microbial detection technologies that are based on biosensors, nanoarrays, Lab-on-Chip platforms and more recently, nanocantilevers. The latter are advanced sensors capable of detecting minute quantities of viruses, bacteria and other contaminants in air and fluids by coating the cantilevers with proteins and antibodies that attract the contaminants. Initially developed for hospital use and in homeland defense applications, nanocantilevers are few microns in length, 20 nm in thickness with thousands of the cantilevers being fabricated on a 1 cm2 chip. Microbial detection is accomplished by measuring changes in cantilever bending or vibrational frequency when contaminants land on the device, causing them to vibrate at a different resonant frequency.
I am constantly looking out for the latest technologies that can detect, enumerate and identify microbial contaminants in pharmaceutical products and manufacturing processes. As such, I have compiled a comprehensive matrix of technologies and workflows for many commercially available RMMs on my educational website, http://rapidmicromethods.com. This is a good starting point for companies wanting to explore rapid methods for their own microbiological applications.
When choosing an RMM method/system what key features/qualities should a pharmaceutical company look for? What are some “must-haves”? What benefits can a modern RMM system provide to a pharmaceutical company?
The benefits a modern RMM system can provide are numerous, including faster time-to result, greater sensitivity or accuracy, better precision and repeatability, automation and sample throughput, to name a few. Additional cost savings or cost avoidances may also be realized when implementing a rapid method.
However, it is not possible to state what the “must have” features should be because this would be dependent upon the end-user’s specific requirements. For example, one end-user may require a rapid method that will detect a single viable cell within 4 hours and process 100 samples in a single shift. Another end-user might require an enumeration result with a limit of quantification of 10 viable cells but do so within a 24-hour period. Therefore, it is up to the enduser to set their own “user requirements” and then match the right technology or system with those requirements in mind.
As the pharmaceutical industry becomes more global in nature – what are some regulatory issues pharma companies must keep in mind when choosing an RMM system for their applications?
Many of the regulatory authorities (e.g., FDA and EMA) have made significant enhancements to policies and validation expectations in order to promote the introduction of new analytical technologies, including rapid microbiological methods. For example, FDA’s 2011 Strategic Plan for Regulatory Science encourages the development of sensitive, rapid, high-throughput methods to detect, identify, and enumerate microbial contaminants and validate their utility in assessing product sterility. Next, FDA’s 2012 Final Rule on Amendments to Sterility Test Requirements for Biological Products permits the use of modern microbiological methods because advances in technology have allowed the development of new sterility test methods that yield accurate and reliable test results in less time and with less operator intervention than the currently prescribed culture-based methods.
In Europe, changes to the Variations Regulations and the establishment of the Scientific Advice procedure make it easier to obtain approvals to utilize alternative methods to conventional pharmacopeia microbiological methods. Most importantly, the introduction of the Post Approval Change Management Protocol makes it possible to submit and gain approval for a rapid method validation and implementation strategy prior to conducting the actual testing. And this new validation approach is very similar to FDA’s Comparability Protocol, which many companies have already applied.
The Japanese and Australian regulatory agencies have also embraced and encouraged the implementation of rapid methods for a number of years, and usually follow similar expectations as FDA and EMA. However, the biggest regulatory “issue” is not associated with regulators per se, but instead lies with a pharmaceutical industry that is generally reluctant to discuss their plans with regulatory authorities and develop a mutually accepted blueprint for success. I always strongly recommend that firms who wish to implement rapid methods discuss their plans with the regulators up front. This way, there are no surprises down the road and everyone is “on the same page” in terms of validation and submission expectations. This is a very simple approach that many companies, unfortunately, do not fully appreciate.
The pharmacopeias have also updated their recommendations for validating RMMs. For example, USP <1223>, Validation of Alternative Microbiological Methods, was significantly revised with an official effective date of December 1, 2015. Some changes in USP <1223> mirror the teachings in PDA Technical Report #33 and the proposed Ph. Eur. chapter 5.1.6 while other changes suggest a substantial shift in the way alternative methods might be validated. The chapter now focuses on method suitability and equivalence while providing the end-user a number of options for demonstrating both concepts. For an in-depth review of the new USP <1223> chapter and how it compares with the other two guidance documents, please see my 2015 APR paper, “A fresh look at USP <1223> Validation of Alternative Microbiological Methods and how the revised chapter compares with PDA TR33 and the proposed revision to Ph. Eur. 5.1.6,” American Pharmaceutical Review. 18(5): 22-35. [http://bit.ly/1oXO5Db]
Data capture and analysis is a big part of the pharma industry. How do RMM systems integrate and interact with data systems to provide pharma companies with the insight they need?
Many of today’s commercially available rapid method systems are designed to integrate and communicate with external servers, LIMS and related IT platforms. Additionally, a number of systems claim to be 21 CFR Part 11 compliant, although it is the end-users responsibility to demonstrate compliance though a robust computer system validation program.
Furthermore, a number of rapid method technologies provide enhanced data handling capabilities, including trending and realtime tracking of recovered microorganisms.
For those systems that do not communicate with external IT platforms, it is worthwhile to discuss your requirements with the technology supplier to determine if a solution can be tailored to meet your needs.
Looking ahead, what do you see as the future for RMM in both the pharmaceutical and biopharmaceutical industries?
Looking to the future, rapid microbiological methods will play an important role in the pharmaceutical and biopharmaceutical industries as well as for other stakeholders including cell therapy manufacturers, compounding pharmacies and positron emission tomography (PET) suppliers where the time-to-result during microbiological analyses must be appreciably reduced. In particular, many PET and cell therapy products have an extremely short shelf life and must be administered or infused in the patient within 24-48 hours after manufacture. This is where rapid methods can play a vital role in supplying the patient with life-saving pharmaceuticals and in a timely manner. As for big pharma, recent outbreaks such as those associated with Ebola and the increasing challenges accompanying the spread of Zika virus may necessitate the use of rapid methods to supply the public with new vaccines and medical treatments. And the faster the industry can release each batch of medicine for distribution is a step in the right direction.
Author Biography
Dr. Michael J. Miller is an internationally recognized microbiologist and subject matter expert in pharmaceutical microbiology and the design, validation and implementation of rapid microbiological methods (RMM). He is currently the President of Microbiology Consultants, LLC (http://microbiologyconsultants.com) and owner of http://rapidmicromethods.com, a website dedicated to the advancement of rapid methods.
For more than 25 years, he has held numerous R&D, manufacturing, quality, business development and executive leadership roles at multinational firms such as Johnson & Johnson, Eli Lilly and Company and Bausch & Lomb. In his current role, Dr. Miller consults with multinational companies in providing technical, quality, regulatory and training solutions in support of RMMs, sterile and non-sterile pharmaceutical manufacturing, contamination control, isolator technology, environmental monitoring, sterilization and antimicrobial effectiveness.
Dr. Miller has authored more than 100 technical publications and presentations and currently serves on the editorial and scientific review boards for American Pharmaceutical Review, European Pharmaceutical Review and the PDA Journal of Science and Technology. He is also an advisor to the USP Modern Microbiological Methods Expert Panel.
Dr. Miller holds a Ph.D. in Microbiology and Biochemistry from Georgia State University (GSU) and a B.A. in Anthropology and Sociology from Hobart College.