IN PERSON
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Danny Levenson is president and chief executive officer at Millenia Diagnostics Inc. (San Diego). Millenia Diagnostics is a biotechnology company that is focused on the supply of research and manufacturing products and services in the field of diagnostics. Levenson oversees development and manufacturing of IVD products and reagents in a variety of technology platforms. He can be reached at danny@
milleniadiagnostics.com. |
In the face of a growing global IVD market, U.S. diagnostics companies need to keep product prices low to remain competitive. One way they can accomplish this without sacrificing quality is by improving manufacturing efficiency—for example, by using equipment that is automated and more reliable. Another way is by outsourcing certain production tasks, allowing them to dedicate more time to their areas of specialty.
However, in taking steps to lower costs, IVD companies must remain mindful of the rapid advances in diagnostic technologies. Any new processes introduced should be flexible enough to accommodate new technologies as they are developed. In addition, companies need to ensure they are meeting the requirements of both domestic and international regulations.
To find out more about the manufacturing and processing issues that diagnostics companies face, IVD Technology editor Richard Park spoke with Danny Levenson, chief executive officer at Millenia Diagnostics Inc. (San Diego). In this interview, Levenson discusses the different strategies IVD companies can use to run more efficiently and meet user demands. He also talks about the realities of FDA regulations and inspections, trends toward multiplexing, and how diagnostics companies should be structured to encourage collaboration and innovation.
IVD Technology: Does Millenia Diagnostics consider itself more of an IVD manufacturer or a supplier to diagnostics companies?
Danny Levenson: We do both. Millenia Diagnostics is a San Diego–based biotech company focused on the supply of research and manufacturing products and services in the field of diagnostics. Our products and services are used by universities, government agencies, publicly traded companies, small private companies, and international businesses. We’re good manufacturing practices (GMP) compliant and recently obtained our medical device manufacturing license. We produce both Class I and Class II medical devices.
What have been the most significant advances and trends in the area of diagnostics manufacturing and processing technologies over the past few years?
Although the idea of lean manufacturing systems is not new to IVD producers, they continue to be employed and refined. In addition to reducing waste, these systems help improve processes. By reducing material cost, streamlining design and manufacturing processes, and improving quality, the domestic IVD industry can stay globally competitive.
Many companies are focusing on their manufacturing equipment to reduce costs and increase quality. Manufacturing personnel are calling out for robust equipment that enhances efficiencies by virtue of its reliability on the production floor.
In addition, there’s been a movement toward custom and automated equipment. The benefits of this include improved reproducibility and the reduction or elimination of labor-intensive processes.
One such company, Kinematic Automation Inc. (Sonora, CA), is an industry leader in equipment for the development and manufacture of rapid diagnostics.
Quality has always been the main attribute of U.S.-based diagnostics companies, but as we’re faced with a global market, pricing is becoming more and more important. Lean manufacturing systems help our pricing to stay globally competitive.
Do increased quality requirements and demands place pressure on the development of manufacturing and processing technologies?
Certainly the increased quality needs impact the manufacturing processes by requiring quality systems such as corrective and preventive action, process control, and validations. These are not just requirements, but are essential to producing consistent, high-quality products. In addition, product development is affected by the implementation of stricter design controls and risk analysis.
Looking at shared technical complexity, what are the most troublesome areas involved in manufacturing IVD products today?
One troublesome area is in using highly variable raw material to manufacture a finished product with low variability. There’s a natural inherent variability in biological reagents as well as in many other materials used in the manufacture of IVDs. Thus, one trend is the movement toward raw materials with greater reproducibility.
For example, polyclonal antibodies, which can have a high degree of variability, are undergoing improved purification processes or are being replaced with monoclonal antibodies, which can be produced with a low degree of variability from one batch to another. Another example is the use of recombinant proteins in place of native proteins. In some cases, natural materials are being replaced with synthetic material.
Controlling raw-material variability leads not only to more readily reproducible end-products but means that less time is spent evaluating materials and making changes to compensate for their variability.
There’s also a movement toward multiplex diagnostic devices that are able to detect numerous agents in a single device. Determination of required reagent concentration becomes more difficult as the number of markers increases.
There’s a risk that higher production costs would arise from rejected components containing numerous high-cost reagents, but this can be controlled with proper preproduction quality control measures.
Multiplexing has been received favorably by the market because of the advantages it offers. From a manufacturing and processing standpoint, what sorts of challenges and complexities are involved in multiplexing?
One challenge is to calibrate all the markers once they’ve been combined. There’s a lot of preproduction work that’s needed to qualify and characterize the raw materials so that when they are manufactured as a multiplex device, all the reagents are calibrated properly.
As the number of analytes the device is intended to detect is increased, calibrating the device becomes even more complex.
You noted that in many cases, natural materials are being replaced by synthetic ones. Are companies able to replicate materials well enough that they exhibit the same properties as their natural counterparts?
Yes. In some cases, they are quite adept at matching—and even exceeding—the performance of natural materials due to their sheer reproducibility.
One example is sample-application pads, which are typically made from a composite of natural materials. There are new synthetic materials in development that are sure to capture the attention of many IVD producers.
Are there different challenges for the chemistry and the instrument sides of IVD manufacturing?
There are definite differences in the challenges faced by the two sides. One such difference is the regulatory challenges faced by instrument makers.
The validation procedures for electronics and software can be cumbersome. On the chemistry side, there’s a greater flexibility in design changes; however, instrumentation makers are faced with more-rigorous validation procedures. The instrument makers have a tougher job of dealing with user interface, complexity of design, and the never-ending demand for a smaller instrument.
Although the obstacles are not as great on the chemistry side, it is still a design challenge to get the reaction chemistries to work as quickly as the end-user and the market demand. The older IVDs were considered rapid if they gave you a result in two hours. Today, point-of-care diagnostics are expected to return results in 10 or 15 minutes.
Facing Regulatory Challenges
According to the quality system regulation (QSR), FDA is obligated to conduct inspections of manufacturing facilities every two years. Have you found this to be the case, and what do these inspections typically entail?
In our experience, FDA absolutely has lived up to its obligations. Millenia Diagnostics has been inspected twice in the last three years.
Typically, these are inspections of three or four of a company’s quality systems. The inspectors choose one or two quality systems that they can look at in depth. Inspectors commonly look at batch records of finished products and trace all of the components that went into them to make sure all the quality systems were used.
How can IVD companies prepare for an inspection?
IVD companies should be prepared for an inspection at any time. Regular internal audits are required, and I highly recommend using the quality system inspection technique (QSIT). This is a guide that’s used to train FDA inspectors on performing their audits. It gives manufacturers a good perspective of what FDA will be looking for and which systems inspectors will want to see.
Can you recall your reaction when you were first confronted with the need to meet FDA and similar regulatory requirements?
At the time, I was in charge of the manufacturing department of a company that was GMP compliant. When the new QSR was put into place, I had the task of taking the company’s quality systems and updating them.
Initially, it felt like an overwhelming task. However, once I made use of the many resources available—both private and through FDA—that feeling quickly faded.
FDA has made many tools available to help companies understand its requirements. Tools such as the QSIT guide provide a great understanding of which systems will be inspected and give manufacturers insights into an inspector’s point of view.
When performing internal audits using the QSIT, companies can easily identify noncompliance and take actions to correct and prevent them. This is a valuable tool that should be used for training all IVD manufacturing personnel.
Another useful tool is The FDA and Worldwide Quality System Requirements Guidebook for Medical Devices. This book provides a great overview of the QSR as well as a comparison chart with GMP and international standards. Taken together, these tools help lead manufacturers toward better compliance.
What other sorts of private resources did you tap into and use?
There are numerous consultants that provide private on-site training. In addition, there are many GMP and quality systems seminars given, to which I routinely send my employees.
Of course, FDA’s Web site is also a good resource and offers a wealth of compliance information.
The regulatory requirements and international standards you mentioned are intended to keep companies from designing and producing bad products. In what ways do these requirements help make technically complex processes simpler for IVD manufacturers?
One requirement—design controls—is an essential part of the design process of IVDs. Regulatory agencies have recognized a lack of design control as one of the major causes of device failures and recall.
These standards helps simplify the complex process of IVD development by calling for the identification and assessment of design requirements that are necessary for developing safe and effective medical devices.
Although IVD development is a complicated process, it is simplified by the establishment of design controls that spell out the starting specifications, as well as the labeling, user, and performance requirements. In addition, these regulations help with the validation of design, the transfer to manufacturing, and the creation of a design history file.
The regulatory requirements guide the production of medical devices from design through release for distribution. Imagine if every company had to come up with its own quality regulations. FDA has done a great job simplifying and standardizing the process by which medical devices are developed and manufactured.
Based on your experience, does FDA change its requirements in order to maintain a level of quality?
In my experience, FDA changes its requirements to maintain product safety and effectiveness. The pace of change allows a company to stay up to date with the GMPs and current regulation. As these regulations move forward, they’re actually becoming less complex. FDA is doing its best to help us understand, as IVD producers, what quality systems we need. As FDA revises its quality system requirements, the tools for complying with them are becoming more useful.
Are regulatory requirements and international standards equally useful when dealing with cutting-edge products?
Sure. Manufacturers are tasked with establishing and complying with quality systems to ensure that their products continually meet specifications. Systems such as corrective and preventive action (CAPA) are valuable tools in high-tech manufacturing environments.
CAPA is used to identify the root cause of nonconformances. In some cases, this may be poor design. The system calls for preventive measures, as well as for validation that the measures are effective.
A good program includes regular follow-up investigations and meetings to discuss CAPA issues and encourages trend analysis to prevent further nonconformity.
CAPA is just one component of the quality system. Quality system components such as production and process controls, facility controls, document controls, and purchase controls are not just requirements, but are necessary for producing high-quality products.
New manufacturing processes will have to be developed as new technologies are born.
To eliminate redundancies, how can IVD manufacturers streamline their compliance activities for FDA and for international standards? Are there still areas where independent efforts are required?
There will always be some independent effort required for compliance between domestic and international standards. Still, IVD manufacturers that are FDA compliant need to make only minor modifications to meet international standards.
Many domestic companies whose products are selling overseas are becoming certified as compliant with the International Organization for Standardization (ISO; Geneva). Registration of a device in each country is done independently and may vary from one country to the next. So, there is still some independent effort required, but in general, the requirements overlap fairly well.
What roles do the ISO standards and other requirements play in an IVD manufacturer’s manufacturing and processing technology?
If a manufacturer is selling products overseas, international requirements play a big role. The main differences between the international standards and FDA requirements are in the labeling, language, and approval process.
How does an IVD company’s organizational structure make the manufacture of a product line easier or more complicated?
I’d say that integration of departments is essential. The trend is to have entire companies committed to high quality, reduced cost, and continued process improvement.
It is not enough to have just the manufacturing department on board. There needs to be cohesion between each department, including research and development, where new products begin to take shape, and the manufacturing team.
The purchasing department has the task of getting better pricing on raw materials, as well as ensuring that suppliers are able to meet in-house specifications. The role of the quality control groups should be not only to pass or reject products, but to advise and educate the manufacturing group about improvements that can be made at each step in the manufacturing process. Finally, the research and development team should consider the ability of the manufacturing group in its design process; this could lead to simpler designs and more manufacturer-ready products.
Deciding to Outsource
Do IVD manufacturers outsource any of their product development or manufacturing activities? What would be the business rationale for such a decision?
IVD manufacturers are increasing their outsourcing activity. Economics, quality, regulatory compliance, and in-house capability are a few key factors to consider in deciding whether or not to outsource.
In addition to its lower cost, outsourcing allows companies to focus on their core competencies such as marketing, business development, intellectual property, discovery and licensing, and distribution.
The cost of outsourcing IVD development and manufacturing can be tremendously lower than performing these activities in-house. To develop IVD products in-house, a company must assemble a knowledgeable team and be prepared to take the time to develop quality systems, to obtain manufacturing equipment, to develop manufacturing processes, to validate processes, to obtain the proper permits and licenses, et cetera.
Contract and research and development organizations can perform IVD development at a fraction of the in-house cost and, just as important, can shorten the time to a commercial-ready product.
It could take a relatively long time and be costly for a company to set up an FDA-compliant manufacturing facility and quality system. However, contract manufacturers are already compliant and have experience navigating through the regulatory environment.
What types of IVD manufacturers tend to outsource their manufacturing activities? Are they typically larger companies or smaller companies?
I’d say that a majority of companies are outsourcing at least one or more components of their IVD product. They tend to be larger companies, but small companies have limited resources and tend to outsource as well.
It seems logical that a smaller company, which may have a great product but lacks the capital to set up its own manufacturing facility, would gain benefits from outsourcing. What is the rationale for larger IVD companies outsourcing their manufacturing activities?
IVD companies look for teams that specialize in areas where they may lack expertise. So, several small companies that specialize in diagnostic development may serve a niche, whereas some large companies are more in tune with marketing, distribution, and intellectual property discovery and licensing. But when it comes to outside development and manufacturing, they look for outsourcing partners.
Outsourcing of manufacturing has been increasing quite a bit. I see this trend continuing.
What experience does Millenia Diagnostics have with contract manufacturing?
We are an outsource for contract development and manufacturing of critical components and finished devices. Some IVD manufacturers outsource many of their labor-intensive tasks overseas, but they tend to keep their most critical components close to home if they have to outsource them. Because IVD companies are more concerned about not losing quality for these critical components, they look for FDA-compliant companies they can visit more frequently.
I would guess that more-complex IVDs require certain complex manufacturing processes. As the trend toward these types of tests continues, what sort of outsourcing challenges will IVD companies encounter? Will it be difficult for them to find the right contract manufacturing partner?
Certainly the outsource partner and the company need to be a good match. But for contract manufacturers and developers, it’s important to stay at the cutting edge of technology. That’s just more of a reason for other companies to outsource their development to your company.
Contract manufacturers must dedicate resources to learning about the technologies that are out there, what the current trends are, and how can they be improved upon.
The Future of IVD Manufacturing
What trends do you think will emerge in the area of diagnostic manufacturing and processing technologies?
I see a trend toward a point-of-care multiplex device—in other words, a point-of-care device that can measure multiple analytes, detect multiple infectious agents, and give more information to the clinician with just one single test.
The challenge for IVD manufacturers and producers will be to generate processes along with these new multiplex diagnostic technologies. The big challenge will be in the calibration of all the markers once they are combined into a single diagnostic test.
The demand for the IVD industry is for more information and for maintaining ease of use.
What types of manufacturing challenges would calibrating multiple markers on a single device present?
Each analyte in a multiplex assay has to be calibrated individually and then combined into a single assay. Then, further calibration may be required due to the influence of the reagents for the other biomarkers.
So, lots of preproduction work and prequalification of reagent processes will have to be completed to ensure that calibration is correct for the end-product.
