For someone concerned with return on investment (RoI) in pharmaceutical manufacturing, how does microbiological monitoring relate to product quality?
TS: Microbiological monitoring plays an important part in assessing product quality, although foremost consideration should be given to environmental and process controls. Through the use of smart risk assessment, monitoring can be orientated to those parts of the process that are theoretically at greater risk. An example would be open processing.
There are different forms of monitoring and each is important. Knowing what is carried in the air can help determine what might be directed or could settle into product; whereas bioburden and endotoxin in-process controls can be used to determine risk points in process. Such data is particularly useful when investigating a contaminated end product.
The extent that this can be quantified or qualified in terms of return-oninvestment is less certain. There are savings that can be made through the use of the "lean laboratory" and with the adoption of more efficient (such as rapid) methods. However, at the end of the day, it is all about patient safety.
TC: Yes, I still hold pharmaceutical stock in my retirement portfolio so I am concerned with ROI! Microbiological monitoring of pharmaceutical ingredients including water, packaging materials, and the manufacturing environment is merely a tool to verify that pharmaceutical ingredients and packaging materials are of high microbiological quality, and water systems and manufacturing facilities are designed and operated in a manner to prevent product contamination. For discussion of bioburden control in non-sterile drug substances and products and the role of microbiological monitoring, I would refer the reader to the new USP Informational Chapter <1115>.
With aseptic filling operations, the factors that are most responsible for the sterility assurance of products are clean room design and operation, facility layout and material movement, robust sterilization processes, effective cleaning and disinfection programs, strategies to separate personnel from exposed product, and clean room personnel training and supervision. With environmental monitoring, the use of alert and action limits that are not consistent with the analytical capabilities of the methods should be discouraged. I predict the industry will eventually move to isolation frequencies as promoted in USP <1116>.
DJ: Often, return on investment analysis considers hard savings such as resources, time, and throughput. Quality is regarded as a softer value point and more difficult to quantify in dollars. However, the quality of products brought to market reflects directly on the brand and the equity of the brand. In industries such as personal care products, which may not have as stringent regulatory requirements for quality testing, those companies will take extra testing steps with the sole focus of protecting or enhancing their brand reputation. To that end, microbiological monitoring ties closely to product quality, and can be quantified as part of the overall value to the company’s brand.
LD: Looking from a pure return on investment perspective, we can say that microbiological monitoring is a part of the cost of quality. Raw materials, work-in-process, and finished products may all be held in quarantine while they’re screened to ensure that they meet their microbial specification. It’s not just the cost of testing but also its operational impact measured by the cost of quarantined inventories and extended lead times that contribute to the cost of ensuring that product quality standards are met. The Cost of Good Quality is the investment made in order to prevent experiencing the Cost of Bad Quality. The Cost of Bad Quality is clear–rework, scrapped materials or product, workflow disruption, lost revenue, and in the worst case, product recall.
Rapid microbial methods (RMMs) play a role in managing both elements of the cost of quality. By screening materials and products faster a company’s microbiological monitoring program has less operational impact reducing the investment in quarantined inventories and extended lead times. And with faster detection, the costs resulting from contamination can be minimized.
RQ: Return on Investment and quality can sometimes appear to be in conflict. Typically, the higher the quality, the greater the cost and the lower the ROI. One piece that needs to be factored in however, is that amount of repeat testing or discarded product that can result from the use of a lower quality method. While the ROI might appear good on paper, the overall negative impact on both the business and the laboratory from repeat testing, delays in testing, or worse, delays in manufacturing or releasing product, can quickly eliminate increased returns.
CP: Accuracy is a major concern in microbial monitoring and lack thereof can seriously impact product quality. Rapid Microbiological Methods (RMMs) are undoubtedly the most powerful tools to help with the monitoring process. There are several high quality systems from different providers available that differ in the underlying principle they are based on, which consequently impacts the accuracy of the results. Genetic methods do have the clear advantage here. They also differ in price. A lower purchase price and low daily operating costs may seem to favor certain systems over others. But, is the cheaper necessarily better or will compromises made based on lower costs eventually jeopardize accuracy and efficiency? In 2009, Michael J. Miller wrote "Rapid Microbiological Methods and Demonstrating a Return on Investment: It’s Easier Than You Think!" (American Pharmaceutical Review, Vol 12, Issue 5, 2009). Miller points out that in addition to the purchase of a RMM, costs for the qualification and validation of the system, the daily operation, training, etc, impact the ROI. A system that works more accurately than others and includes meaningful services and features will help with the downstream implementation and is ultimately the better choice despite possible higher initial costs. Any good ROI calculation needs a good financial model that considers all expected costs.
FDM: Microbial monitoring is a key component of Product Quality management. Lapses in monitoring lead to potential product contamination, which can be costly for the manufacturer and involve expensive investigations and corrective actions.
Environmental monitoring supplies crucial information to ensure environmental parameters are maintained within set target ranges, to avoid unknown bioburden in surface, air, water, and personnel that ultimately could drive to product quality failure. Understanding the environmental bioburden can also assist, and potentially save time and resources, during investigations. The data provided by microbiological monitoring helps establish that the process is under control which can only lead to increased product quality.
It is not always better to test more; it is definitely to be better at testing, with accurate set of tools to provide the information for recurring decisions, day after day, as well as bringing additional critical information necessary during an OOS.
Working with your vendors to provide the right products could help you make the next steps on saving time and resources. High-end innovations, as well as classic tools, can also help. I would like to give just a simple example. A culture media, as a basic tool and so important in its purpose for a microbiological monitoring program, can bring high loss of efficiency if its performances are not optimum at any time from the moment it is received, to the moment it is actively used. The capacity of such a plate to be stored at flexible temperature could minimize the overall cost of the program, and is better adapted to any production process flow. Also, being able to secure and demonstrate the stable performance of that plate over the time in stringent conditions with robust neutralizing effect is again driving efficiency.
Why is microbial identification important in efforts to maintain a non-sterile manufacturing environment?
TS: Characterizing and speciating the microorganism is important in three ways. First, the species provides information about the whether the microorganism is likely to survive or reproduce in the product. Secondly, assuming that the microorganism can survive and proliferate, it enables the risk to the patient population to be considered. Thirdly, knowing the species provides clues as to its origins, and this helps with formulating preventative actions as part of a microbial data deviation.
The assessment of the origin of contamination may result in the need to assess whether or not two microorganisms are the same. The only sure way to do this is through genotyping, and here there are some more advanced geneotypic identification systems on the market.
For other aspects, phenotypic identification is sufficient enough for considering process or environmental control. It is important that microbiology laboratories employ staff with sufficient identification skills; this is something that should not be skimped on.
TC: In non-sterile manufacturing areas, microbial identification to species is actually not that important for air and surface monitoring. After the most frequently found bacterial isolates have been initially identified, characterizing ongoing isolates by Gram reaction and cellular morphology is usually sufficient.
However, when confronted with product failure due to microbial contamination, speciation of microorganisms found in the product will provide insight to the source of these contaminants and how they can be remediated. In my experience, usually they originated from the equipment train, excipients, or ingredient water and not the general facility or operators.
DJ: Good manufacturing practices dictate that in the event of an out of specification event, the micro-colonies observed should be identified. Identification helps the lab implement mitigation strategies to avoid any future similar contaminations. Identification also helps to determine the source of the contamination. Sometimes an investigation will determine that the contaminant came from personnel, not the environment or manufacturing, creating a training issue vs. a site cleaning. Knowing the micro-organism that caused the out of specification event can reduce the time needed to determine the cause.
RQ: As cited in multiple USP and FDA guidance documents, microbial identification is important in maintaining proper control of a non-sterile manufacturing environment for a few key reasons. It is important to understand what control of the manufacturing environment looks like, so that steps can be taken should the environment be deemed out of control through the appearance of organisms not previously identified. If the types of microorganisms change, it can result in the need for a change in disinfectants, along with a possible evaluation of the cleaning and/or testing requirements.
CP: There are not many regulatory requirements for microbial control in the manufacture of non-sterile pharmaceutical products. One way to add control is to create a risk-based approach that defines where microbial contamination could occur and what types of organisms are introduced by using appropriate control and monitoring methods. A rapid, accurate microbial identification system is a critical component of this program as accurate identification of organisms isolated from the manufacturing environment or product is the first step in remediation of the problem.
FDM: Implementing a risk based approach similar to HACCP, and gathering regular and consistent information on the bioburden allows for trending data and corrective actions to be put in place, avoiding the risk of major contamination event.
What are the challenges involved in resolving microbial contamination?
TS: The biggest challenge is determining where the contamination has arisen from. Sometimes this is straightforward, such as standing water; at other times it can be like the proverbial "needle in a haystack," such as eventually tracing an airborne microorganism to a tiny hole around the seal to an air handling unit. Experience is important, and so is a structured approach.
Once contamination has been identified, the challenges relate to the type of product. With sterile products any suspected contamination is a problem and this is automatic batch rejection. With non-sterile products there are various steps to be taken. Much of this centers on whether the microorganism can be classed as "objectionable" (and defining this depends on the product). To complicate this further, information stemming from the Human Microbiome Project is suggesting that the interaction between drug products and microorganisms needs to be considered on a patient-by-patient basis. This is not so much in terms of contamination causing direct harm, but the extent to which a drug may or may not work within the human body.
TC: As I see it, the biggest challenge is moving microbiologists from a laboratory testing mode of operation to a risk-based mode of thinking. Risk mitigation should be a major consideration during ingredient selection, formulation development, manufacturing process design, and routine production and testing. Microbial testing must be directed toward mitigating risk. Microbiologists, the quality unit, and manufacturing should appreciate which dosage forms are the most susceptible to microbial contamination, exposing patients to the greatest risk of infection, and the relationship between unit manufacturing steps and bioburden control, and allocate their resources accordingly.
DJ: Data drives the investigation to resolve a microbial contamination. The more data surrounding the event, the better equipped the microbiologists are to address and resolve the issue. Having the colony available to identify the micro-organism and the use of rapid ID methods helps speed up determination of cause. In the case of environmental monitoring, the use of historical trends can point to potential “hotspots” where the levels may be steadily increasing. When this data is captured manually, the research takes longer and can lengthen the investigation. If the sample had been destroyed during testing, the re-culture and sampling step also adds time.
LD: Once microbial contamination has been detected, the next challenge is to find and contain the source as quickly as possible. This isn’t always straightforward and becomes more difficult as time passes. From there the challenges relate to identifying an effective corrective action and being able to implement preventative measures. This is another area where RMMs have value. The sooner contamination is detected the lesser its impact and the greater the probability that the source can be identified and a corrective action put in place allowing processes/production to resume. But the benefits of RMMs go far beyond just getting results faster. As an example, we find instances where Celsis users are adding or increasing their in-process testing with a positive-release because they can get those results in 24 hours instead of 3 to 5 or even 7 days. The risk/cost/benefit analysis changes with 24 hour results.
RQ: One of the biggest challenges is making sure that all key stakeholders are involved in the resolution. While the microbiology laboratory has a great deal of knowledge about the contamination, they can be a key driver to the resolution, but need to have members of production, quality, and the overall business involved to ensure that the appropriate buy-in from each group is achieved to effectively resolve the contamination. Key to this challenge is clearly identifying the root cause of the contamination, so that it can be stopped and the source of the contamination remediated so that it cannot continue after this resolution. Decisions driven by data provided by the microbiology laboratory can help ensure that the problem is correctly identified, a proper remediation plan established based on the contamination, and resolution confirmed.
CP: The manufacture of biologic products is subject to contamination by agents such as bacteria, fungi, and viruses. Contaminations can cause product variability, the loss of potency due to degradation or modification of product or can lead to serious safety concerns. Not to mention the financial burden to the manufacturer. Often lengthy investigations to identify the root cause for the contamination are necessary to prevent reoccurrence. Appropriate contamination control requires methods that can identify the contaminants quickly, accurately, and reliably. This is necessary to determine the microbial entry point within the process, the source of the microbial contamination, the growth behavior of the microbial agents, and ways to eradicate them. Anything less will ultimately lead to failure.
FDM: Probably one of the biggest challenges is identifying the source of contamination. Once a contamination has occurred it may take days or weeks to find its source, and more to confine it and withdraw it. Meanwhile the cost—in terms of resources, the time spent identifying, and the implementation of corrective actions—rises. Maintaining accurate data records and trending information will help provide future benefits such as potential areas of constant contamination, which can then be proactively modified.
What are some of the current innovations in microbiology testing and sterilization?
TS: With microbiological testing there has been some good progress with real-time air sampling, where spectrophotometric devices can distinguish between inert and viable particles. I think that the next area where there will be progress is with real-time microbial counting of water, where flow cytometry can be taken to a new level. To add to these, there is some excellent technology for environmental monitoring that can detect microbial colonial formation much earlier than conventional methods. Anything that can reduce incubation times is a good thing.
With sterilization, the innovations are with alternative methods of sterilizing. Whether there is a need for some of the emerging technologies and how effectively they might replace existing mainstream technologies is debatable. Nonetheless, electron beam has some potential for the sterilization of plastics without some of the residue risks that can arise with ethylene oxide or the brittleness that can occasionally occur following gamma irradiation. X-rays provide a similar application, for plastics.
Some studies have been undertaken using bursts of broad spectrum white light, delivered at high intensities, to sterilize products within their final containers ("pulsed light"), which looks interesting. Finally, the application of supercritical gases is of interest for sterilization because it has been shown to have anti-microbial effects at high pressures.
TC: Innovations in microbial testing that impress me most are MALDI-TOF mass spectrometric approaches to microbial identification, real time PCR screening of target groups of respiratory, intestinal or blood borne pathogens, and laser-induced fluorescence methods for real time water and air monitoring. The first two technologies were pioneered in clinical microbiology and the third in bioterrorism detection but they will have enormous impact in the pharmaceutical industry in the near future.
As to sterilization innovations, I like the changes around the migration from vials to pre-filled syringes. These include online electron beam sterilization of the syringe components, syringe filling within restricted access barrier systems (RABS), and vision systems for filled syringe inspection.
However, I have long been concerned, as are the regulators, about the over reliance on aseptic filling of sterile injectable products. To this end, I have a review article in the July-August, 2014 PDA J. Pharmaceutical Science and Technology on the justification of aseptic filling over terminal sterilization.
DJ: The introduction of automated methods has offered an option to the microbiology lab that addresses many of the common issues with which microbiologists struggle. The traditional culture method for testing has been the gold standard for more than a century. The addition of automation to perform the compendial method retains the best of the method (non-destructive, reporting in CFUs, same sample prep) and removes error and resource requirements. This allows microbiologists to support increasing workloads with the same resources without sacrificing the quality of their work or accuracy of their results.
LD: One of the biggest changes in microbiology testing in the pharmaceutical industry is the adoption of rapid methods. Celsis has worked with companies in the food and personal care industries since 1992 and it’s only in the past several years that pharma has begun to embrace RMMs. To a large extent this has been because of conservatism of regulators and the absence of a well-defined approach to validation and regulatory approval. That’s changed as expectations have been clarified and some of the more innovative companies have been willing to share their successes. More and more we see regulators at the podium of industry conferences encouraging the adoption of rapid methods and answering questions about suitable approaches to implementation. This is happening not just with the FDA and European regulators but other regulatory agencies around the world and is a trend that we expect to see continue.
Still focusing on RMMs, the other innovation has been the development of pharma-centric applications. For Celsis, that has meant taking our highly sensitive AMPiScreen technology and developing additional protocols that broaden its suitability. For example the use of a wider range of broth types and sample treatments in bioburden testing and its use in sterility testing with anaerobic enrichments, closed-membrane filtration, etc.
RQ: In regards to microbiology testing, the trend is towards rapid microbiology methods. While pharmaceutical manufacturers are comfortable with the gold standards of media-based testing, advances in technology have allowed for application development specifically for pharmaceutical manufacturing needs. Combined with increased regulatory acceptance, technologies such as flow cytometry are now finding their way into pharmaceutical microbiology laboratories.
CP: A wide range of microbiological tests are available for environmental testing but also to assess raw materials, in process, and finished products. In recent years, most of those tests can be linked to automated systems that significantly lower the time to results, minimize human errors, and at the same time increase sensitivity or accuracy. Results reporting is often coupled with realtime communication to allow for immediate action. Methods that rely on genetics (eg, PCR based assays and DNA sequencing) have seen an enormous increase in popularity mainly because of their accuracy and time to results compared to physiological methods.
Requirements for sterilization techniques are well defined (eg, in the ISO 13485, 11137, & 11135 standards). Sterilization techniques are challenging when they have to go beyond the regular autoclave approach, eg, for items that cannot withstand heat. Some of the most common techniques are treatment by dual electron, E-beam, and Ethylene-oxide sterilization.
FDM: One of the latest innovations is definitively providing the discriminating power of MALDiTOF technology for microbiological identifications, offering results in minutes directly in the hands of the stakeholder in charge of corrective actions. Adding the robustness to identify multiple types of organisms, eg, molds and bacteria with limited sample preparation drives to significant efficiency improvement.
On the other hand, even basic products such as culture media have been transformed with the ability for flexible storage, improving neutralizing capabilities to limit the diversity of culture plates used in the plant, and increasing robustness and efficiency in the processes.
Also, increasing productivity of reading plates and reducing traceability bottlenecks which reduce operator fatigue start to be possible from different vendors.
A technology worthy of future exploration could be FilmArray™ PCR, offering the potential for simultaneous detection of molds, viruses, parasites, and bacteria from a variety of products.
What are some of the difficulties in implementing new alternative methodologies in microbiological monitoring?
TS: In theory there are no major difficulties. Some of the technologies are now quite mature and there is an increasing body of evidence as to their effectiveness in terms of papers and reports. Having said that, some technologies are clearly better than others and some are more suited to different applications or products.
To my mind, the main obstacle is conservatism within industry and the need to know whether a rival company has made the conceptual leap to adopting a rapid method. Another reason for slow progress is insufficient resource. It seems that many companies buy new technologies yet they do not have sufficient resources to develop them and implement them into the core laboratory.
Overall, I think that many of the companies bringing out alternative microbiological methods are doing a good job and the methods are backed up by good qualification packages.
TC: Perhaps we have made the method validation process too complicated. For this I must bear some of the responsibility as the chair of the PDA task force that wrote the 2000 technical report on the validation of alternative microbiological testing methods. To address these concerns, the USP Microbiology Committee of Experts published in the July-August, 2014 Pharmacopeial Forum an in-process revision to USP <1223> that discusses implications of signals other than the colony-forming unit that are used in rapid microbial methods. Furthermore, the chapter introduces the four concepts of acceptable, performance, results, and decision equivalence for the demonstration of equivalency as alternatives to classic growth-based microbial methods. This should help.
DJ: Companies with whom we speak often have concerns around the validation of any new technology. Primarily, they are worried that the validation will strain resources and that regulatory bodies are not open to new methods. This is changing. As more labs validate their methods for routine use, it is clear that regulatory authorities are open to new methods in microbiological monitoring. In addition, with the introduction of the Revised PDA TR33 document, some areas of validation concerns have been clarified to help streamline the validation process. Some method providers will offer their resources and documentation to further streamline the process.
LD: Implementation begins with selecting a system that meets the testing needs considering both the method’s product and application suitability and its practical integration into the production facility.
Many companies also struggle with defining the appropriate validation protocol considering the level of regulatory oversight, raw materials versus finished products, over-the-counter versus prescription drug. Guidance exists from the pharmacopeias and industry groups (USP <1223>, EP 5.1.6, PDA TR33) and the system vendor should be able to provide support as well. Perhaps the greatest difficulty that companies face is finding the resources to complete validation and implementation. To address these difficulties, Celsis has developed a comprehensive implementation package that includes IQ and OQ protocols, DMFs and Technical Reports, and Validation Protocols. We also staffan Applications Development lab and have partnered with several leading GMP contract labs that have been trained to provide contract validation services of our system.
RQ: Recent data points towards the major difficulty in implementing an alternative microbiological method not being unclear validation requirements or economic reasons, but rather to the lack of developed applications specifically for pharmaceutical manufacturing. As more rapid methods are being shown to have been developed for specific a pharmaceutical applications, as opposed to trying to make another technology fit into a pharmaceutical microbiology laboratory, more pharmaceutical companies are beginning to adopt and implement these methods. Support from instrument and reagent manufacturers is key, not only in providing the specific application or feasibility information, but also in helping to provide method development or validation guidance and business justification.
CP: The implementation of new methodologies can be held back to a great extent by the lack of willingness to move away from long established, but perhaps outdated, methods. Also, the classical microbiologist has traditionally had very little to no exposure to more modern methods that are based on molecular genetics. Discussions about the advantages or disadvantages of certain methods can become more an issue of personal opinion rather than a scientific argument. In other cases the implementation of alternative methods could require additional changes in some areas, eg, sampling, sample processing, analyst training, and SOP updates or revisions. These process updates can add to the timelines required for updating methods or addition of new systems. An important consideration when evaluating new technologies is discussing and understanding the level of support a vendor can provide, including SOP’s, analyst training, implementation programs, and validation services.
FDM: Validation is probably the biggest bottleneck I see, in terms of the following:
- Resources: More companies have less head count to work with, and validation causes a strain on existing resources
- Time to complete the project and the scope of validation
- Cost (this is often unbudgeted when looking at capital expenses)
- Complexity (depending on the instrument)
How do to the PQ? What organisms should be used? What should be the reference methods? What supporting documentation does the vendor have ? We have seen an increased use of third parties to speed up the validation process while working with the customer to implement the necessary SOPs.