Progress 06/01/15 to 01/31/16
Outputs
Target Audience:Our target audiences reached during this reporting period included several owners of small and mid-size farms who will be served by the development of Dietary Supplement good manufacturing practices (cGMP) and cost effective Raman analytical instrumentation, including a Wyoming herbal supplement farm-based manufacturer, a Wyoming farm producer, and two Missouri farms who are considering manufacturing operations. The Phase I target audiences served by the project are in rural areas in Wyoming and Missouri. We were also in discussions with an herbal manufacturer in Colorado. Though we did not specifically target population groups who are socially, economically, or educationally disadvantaged, the results of this project are intended to benefit the owners of small and mid-size farms who may only produce herbs on a few acres and tend to be more economically disadvantaged compared to owners of larger farms. Changes/Problems:As we started collecting plant samples for the Raman spectroscopy analysis during the first two months, we realized that for Raman spectroscopy to be successful as an identification method for herbal materials, it needed to be able to precisely identify an herbal material (e.g., Ginkgo Biloba) from many different suppliers and from any type of source, such as from leaves, flowers, roots, or a mixture of those. This guided our efforts to have as many different grown, collected, and commercial samples as possible for each herbal sample tested. We narrowed our focus and tested fewer herbal materials, and then narrowed that focus even further. The Raman testing must be discerning enough to uniquely identify what makes a certain genus and species of plant that plant and no other, even if a plant material comes from different sources or suppliers. Our subcontractor is now working with multivariate analysis to isolate the important "peaks" that are unique to the plants being studied in Phase I, and promising results are being achieved. We will send selected samples out for contract analysis testing if necessary to better understand how to effectively identify characterize herbal materials. We expect that the proprietary data analysis method that is being developed during Phase I will be discerning enough to differentiate whether the material is sourced from stem, leaf, or root of the plant; however, it has been a slower development process than we expected. Though we do not consider this a change in our foundational approach, it is important to note that we have found that our library development for herbal materials is much more challenging than it would be for pharmaceutical materials. For instance, a manufacturer may order a material from a supplier that says "Black Walnut," but if the Raman technology does not have in its library all of the different forms that black walnut can take (hull, green outer hull, hull and green outer hull, leaves, or a combination of these components), it may not recognize the herbal material as Black Walnut if the supplier has a different formulation. Because the research pathway for development of the Raman library is taking longer than expected, the hand-held spectrometer software was not ready for use for the scheduled farm demonstrations. Instead, our subcontractor sent an experienced Raman applications specialist to operate the equipment and manipulate the data for our demonstration of the technology. What opportunities for training and professional development has the project provided?We believe that the process of developing the cGMP documentation has helped our farm participants better understand how to comply with the FDA regulations surrounding herbal supplements (dietary supplements). Our focus on developing the best educational materials for farmers and farm manufacturers is expected to be a constant source of training and professional development within the commercial product itself. At every step as we collect more resources and documentation for the farmers and farm manufacturers, we become aware of the sheer magnitude of materials that are available on the Internet from industry sources, through Extension Agents, through the USDA, and from the farmers and manufacturers themselves. Our goal is to organize and present these resources so that farmers and farm manufacturers can "train themselves" and find the best resources possible quickly and easily. How have the results been disseminated to communities of interest?We are not reporting the results to communities of interest yet, as the results remain confidential at this point. What do you plan to do during the next reporting period to accomplish the goals?As we started collecting plant samples for the Raman spectroscopy analysis during the first two months, we realized that for Raman spectroscopy to be successful as an identification method for herbal materials, it needed to be able to precisely identify an herbal material (e.g., Ginkgo Biloba) from many different suppliers and from any type of source, such as from leaves, flowers, roots, or a mixture of those. This guided our efforts to have as many different grown, collected, and commercial samples as possible for each herbal sample tested. We narrowed our focus and tested fewer herbal materials, and then narrowed that focus even further. The Raman testing must be discerning enough to uniquely identify what makes a certain genus and species of plant that plant and no other, even if a plant material comes from different sources or suppliers. Our subcontractor is now working with multivariate analysis to isolate the important "peaks" that are unique to the plants being studied in Phase I, and promising results are being achieved.We will send selected samples out for contract analysis testing if necessary to better understand how to effectively identify characterize herbal materials that may vary because of age, growing conditions, plant part, sub-species, geographic area, or other variables. We expect that the proprietary data analysis method that is being developed during Phase I will be discerning enough to differentiate whether the material is sourced from stem, leaf, or root of the plant; however, it has been a slower development process than we expected. Though we do not consider this a change in our foundational approach, it is important to note that we have found that our library development for herbal materials is much more challenging than it would be for pharmaceutical materials. For instance, a manufacturer may order a material from a supplier that says "Black Walnut," but if the Raman technology does not have in its library all of the different forms that black walnut can take (hull, green outer hull, hull and green outer hull, leaves, or a combination of these components), it may not recognize the herbal material as Black Walnut if the supplier has a different formulation.Because the research pathway for development of the Raman library is taking longer than expected, the hand-held spectrometer software was not ready for use for the scheduled farm demonstrations. Instead, our subcontractor sent an experienced Raman applications specialist to operate the equipment and manipulate the data for our demonstration of the technology.
Impacts
What was accomplished under these goals?
Under Objective 1, to develop easy-to-use documentation for cGMP compliance, we have developed an outline and much of thedocumentation required for a generic set of cGMP (current Good Manufacturing Practice) in word format. This documentation is intended to help small farm manufacturers align with cGMP requirements in their operations every day, and provide generic forms that can be adapted for specific use. We have also researched and selected an open-source form software program that will enable us to translate the cGMP documentation from word format to a workflow process for effective online use. Under other Objective 1 Tasks, we have designed and are documenting a farm-focused manufacturing platform that will encourage regional manufacturing facilities to form around groups of farmers who will grow many of the herbs needed for the manufacturing operations instead of ordering herbs from overseas. We have collected resources for growing and harvesting herbs for the growers, and for the basic requirements for manufacturing for farm manufacturers. We have had collaborative discussions between the farm groups about what process would work best to expand this type of system to other areas and to encourage manufacturing utilizing the herbs and medicinal plants that grow best in any particular area. Two of the participant farms are advancing toward cGMP compliance, with one farm receiving ongoing documentation to fill in its "cGMP gaps" in documentation in word or excel format for the Phase I, and the other updating a shed facility to commercial kitchen standards so that is can become a regional herbal manufacturing facility. The owner of the third farm, after reviewing the process for cGMP compliance, has decided that it wants to focus on its core mission, growing crops and herbs, and is not interested in becoming a manufacturing operation. This farm remains a valuable resource for the project because they represent the farming perspective. The second Objective is to demonstrate the feasibility of developing more cost-effective, robust and easy-to-use analysis equipment to meet cGMP requirements. We have grown, collected, purchased, and harvested many dozens of herbal material samples during the first months of the project. Multivariate data analysis on these samples by our subcontractor is ongoing. They have tested the Raman equipment with selected herbs and demonstrated its potential and capabilities for identity testing that is superior to existing methods at one of the participant farms in October. They have also been working to simplify the instrument design, and have been able to reduce its projected cost by 75%, from a current cost of $22K to ~$5-6K.
Publications
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Progress 06/01/15 to 01/31/16
Outputs
Target Audience:Our target audiences reached during this reporting period included several owners of small and mid-size farms and farm-based manufacturers who will be served by the development of Dietary Supplement current Good Manufacturing Practices (cGMP) and cost effective spectroscopy analytical technology. These included a Wyoming herbal supplement farm-based manufacturer, a Wyoming farm producer, and two Missouri farms who are considering manufacturing operations. The Phase I target audiences served by the project are in rural areas in Wyoming and Missouri. We are now in discussions with other manufacturers who would like to utilize this cGMP technology and spectroscopy analytical identification methods. Though we did not specifically target population groups who are socially, economically, or educationally disadvantaged, the results of this project are intended to benefit the owners of small and mid-size farms who may only produce herbs on a few acres and tend to be more economically disadvantaged compared to owners of larger farms. Changes/Problems:One major change in our approach was driven by our discovery during the Phase I project that the manufacturer has sole responsibility for cGMP. This modified our final two tasks so that we evaluated the value of the cGMP from a manufacturing perspective rather than from a farm perspective. We also updated tasks and metrics to more accurately measure success to fit our increased understanding of the cGMP regulations and of the capabilities of Raman spectroscopy. For the first Objective, we updated our research to focus on compliance from the farmer manufacturer perspective rather than from the grower perspective. We found that small manufacturers face signficiant hurdles in accessing the resources they need to comply with cGMP. A critical finding and change in our focuswas that it became more important to work on compliance from the perspective of what inspectors and auditors expect to see, rather than what manufacturers want to use. There was a great deal of confusion on the part of manufacturers on exactly what was required for compliance; this confusion is reflected in many publically available mainstream articles about how herbal manufacturers are not sure exactly what they need to do for cGMP compliance. We learned that our original metric to have a 75% approval rating from farmers and manufacturers was meaningless if it did not enable them to meet cGMP requirements that inspectors wanted to see implemented. The second Objective was to demonstrate the feasibility of developing more cost-effective, robust and easy-to-use analysis equipment to meet cGMP requirements. Our original goal was to develop a library of 30 grown/processed herbal materials of different types. Growers would organoleptically identify these plant materials and we would compare their ability to identify materials to the Raman spectroscopy method. What we learned during the Phase I project because of our extensive plant sampling process was that there was the potential to develop a highly specific and scientifically rigorous identification method for plant materials that did not currently exist, but there was a catch: We could not simply sample varieties of plant materials and bring them into a "library" if we wanted to develop a system that would accurately verify plant materials with high specificity. The initial testing employed a large number of commercial samples and collected herbal materials from farmers to provide the largest possible sampling of plant materials with the limited budget of a Phase I project. We found that the development of a method of identifying herbal materials was much more challenging than it would be for pharmaceutical materials. Plant materials are chemically complex, and they share many constituents such as cellulose. Because the research pathway for development of the Raman library took longer than expected, the hand-held spectrometer software was not ready for use for the scheduled farm demonstrations; Instead, our subcontractor sent an experienced Raman applications specialist to operate the equipment and manipulate the data for our demonstration of the technology. For Raman spectroscopy to be successful as an identification method for herbal materials, it must be able to precisely identify an herbal material (e.g., Ginkgo Biloba) from many different suppliers and from any type of source, such as from leaves, flowers, roots, or a mixture of those. In the last half of the project, the spectroscopy methods were refined to be better able to identify the plant materials, and we developed a process recommended by experts to verify the herbal materials so that the method would represent a scientifically rigorous and specific method of identification to meet FDA cGMP requirements. Between the Interim report and the final report, we sent selected samples out for contract analysis testing to better understand the characteristics of samples of interest. Another challenge we encountered was a needed change in the instrumentation from one equipment model to a more expensive spectrometer. This change made us examine alternatives to instrumentation for identification much more thoroughly, and we designed a cGMP identification workaround that we discovered during Phase I that should enable the smallest farm-based manufacturers to meet cGMP identification requirements without the use of analytical equipment. By the end of the Phase I project, results were obtained from laboratory testing that significantly improved the data analysis and refined the process for the targeted herbal samples. By adapting our goals and tasks to take into account the complexity of the plant materials and what we learned about cGMP requirements, we have developed a proprietary data analysis method that is discerning enough to distinguish between two plants of the same species, and between several different plant materials at a time. What opportunities for training and professional development has the project provided?We believe that the process of developing the cGMP documentation has helped our farm participants better understand how to comply with the FDA regulations surrounding herbal supplements (dietary supplements). Our focus on developing the best educational materials for farmers and farm manufacturers is expected to be a constant source of training and professional development within the commercial product itself. As we collected more resources and documentation for the farmers and farm manufacturers, we became aware of the sheer magnitude of materials that are available on the Internet from industry sources, through Extension Agents, through the USDA, and from the farmers and manufacturers themselves. What we learned in Phase I research has guided our plans for Phase II, to organize and present all cGMP resources so that they are educational resources and not just compliance resources. How have the results been disseminated to communities of interest?We are not reporting the results to communities of interest yet, as the results remain confidential at this point of our development. What do you plan to do during the next reporting period to accomplish the goals?
Nothing Reported
Impacts
What was accomplished under these goals?
By the final reporting period, Blue Meadows had completed many more forms for cGMP compliance under CFR 21 Part 111 (FDA Dietary Supplement regulations), and updated forms in response to feedback from our consultants. We selected an open-source workflow program and investigated it for its capabilities to work for cGMP development, and to align with the forms that had already been completed. A sample workflow was prepared for our FDA consultant and tested for feedback, and we worked on the design of the farm-based manufacturing platform that would help the smallest manufacturers meet cGMP. Two of the three participant farms continued to work toward cGMP compliance, and the other affirmed the decision never to become an herbal manufacturer because it was "much too difficult" to meet the requirements. This was so even though the farm team had just finished its first round of organic certification with a substantial amount of regulatory paperwork. An innovative tiered approach to forms development was designed, and a multi-faced approach to frame the cGMP forms with context and educational resources to help farm-based manufacturers understand cGMP compliance more effectively. We discovered during our research and construction of forms that it was very important to work on compliance from the perspective of what inspectors and auditors expect to see, because there was so much confusion on the part of manufacturers on exactly what was required for compliance Our original plan to demonstrate a 75% approval rating was modified, and we instead resented our forms and workflow to our FDA consultant for approval, because we discovered during the Phase I research that having a 75% approval rating from farmers and manufacturers was meaningless if it did not enable them to meet the cGMP requirements that would be expected by inspectors. We found that the manufacturers were not aware of which forms were optional and which were required. We did have a high approval rating from our primary farm and manufacturing participants, since they signed up for participation in potential Phase II work. We eliminated one manufacturer from participation because their products were produced solely from imported herbs and raw materials from overseas. Though we know that the development of our technology can help this type of company, its focus on using only imported herbs and raw materials is not within the parameters of our small- and mid-size farm focus. The manufacturer didn't tell us this information until the Phase I was in progress. One other small farm manufacturer who had signed up to participate was not responsive to repeated emails or communications once the project started, and so we were not able to work with them. The second Objective was to demonstrate the feasibility of developing more cost-effective, robust and easy-to-use analysis equipment to meet cGMP requirements. We grew, collected, purchased, and/or harvested over a hundred herbal material samples during the first months of the project. The first half of the project focused on bringing in as many plant materials as possible to the model, whereas the last half of the project concentrated on refining the model and determining its effectiveness, specificity, and accuracy. For Raman spectroscopy to be successful as an identification method for herbal materials, it needed to be able to precisely identify an herbal material (e.g., Ginkgo Biloba) from many different suppliers and from any type of source, such as from leaves, flowers, roots, or a mixture of those. This guided our efforts to have as many different grown, collected, and commercial samples as possible for each herbal sample tested. As the Phase I progressed, we narrowed our focus and tested fewer herbal materials, and then narrowed that focus even further. The Raman testing must be discerning enough to uniquely identify what makes a certain genus and species of plant that plant and no other, even if a plant material comes from different sources or suppliers. During the final reporting period, we sent many samples, especially suspect samples, for outside analytical testing. As we found out that 15% of our tested commercial samples (which are supposed to be accurately identified as the material on the label by the manufacturer), tested as inconsistent with the materials that they were supposed to be. The results of the analytical tests improved the identification model significantly and cleared up some confusing results that we had obtained in the first months. In the last half of the project, the spectroscopy methods were refined to be better able to identify the materials in question, and we developed a process recommended by experts to verify the herbal materials so that the it would represent a scientifically valid method of identification and more effectively meet cGMP. We found that accurate and specific identification for herbal and other plant materials is much more challenging than it would be for pharmaceutical materials. One important conclusion of the Phase I research was that it was not possible to use less expensive spectroscopy equipment because of the complex characteristics and fluorescence challenges of plant material. By the final reporting period, the conclusion was that a more expensive spectrometer instrument than we originally planned to use was needed to be able to accurately distinguish plant materials from each other. We continued to explore methods to optimize the equipment and reduce the cost for a commercial instrument. We also finished design development of an alternative method for cGMP identification compliance that would not require companies to use analytical equipment. We expect that the development of this method and the expansion of the resources we collected during Phase I will support the smallest manufacturers, enabling them to feature and produce farm-grown products and meet compliance requirements for cGMP without requiring the purchase of analytical equipment. One of the critical findings of the Phase I project was that our success metrics needed to be updated to truly represent success for our identification method. We were planning to measure the ability of the farmer participants to identify plants by genus and species, and compare that to our spectroscopy analysis system. Instead, we found out that only manufacturers have responsibility for this identification under cGMP, and that there were specific rules for this identification that made our success metrics irrelevant. Additionally, we found out was that spectroscopy was not highly regarded for herbal identification in the industry because it did not have a good reputation for specificity. This meant that even if we met our original objective to provide 100% validation of 27 out of 30 of the grown/processed herbal materials of different types, it would be a meaningless measurement if other plant materials matched those identified herbs. In other words, we might be able to say "this spectral signature represents rosemary," but if licorice matched the rosemary spectral signature too closely, the identification method would not be specific enough. Whether herb farmers could identify plants or not also became unimportant as we learned more about cGMP--our goal became to provide a verified method of herbal identification using spectroscopy that would pass the most rigorous scientific inspection, and an organoleptic method that would meet the same requirements for smaller manufacturers who could not afford to use analytical equipment, and we believe that we have met both of those metrics through our Phase I work.
Publications
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