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Posted by: jhildreth	6/29/2007 8:11 PM
I am happy to announce the publication of a SOP on Voucher Speciments in the journal of Analytical and Bioanalytical Chemistry that was funded by NIH. This project was a collaborative effort between several groups and hopefully the beginning of many more such informational articles for our industry. The key points I am hoping to convey to the industry is that this protocol was accepted and published in a "peer reviewed" journal which gives it substantial weight in the eyes of FDA. The passing of GMPs have created a huge business opportunity for the selling of chemical reference standards and botanical reference materials. Unfortunately there are no regulations or qualifications needed to sell these materials at least in the dietary supplement industry. What some companies are calling primary standards or botanical reference materials fail to meet the criteria that NIST, USP, NRC etc. have established as foundational to the development of such materials. There have been several incidents of compromised reference materials sold on the market which have affected us all in a very negative way. Once such example is chondroitin. The main company that people were buying reference material from had switched vendors and actually moved to a higher purity material than they had before. Unfortunately, due to a failure to properly characterize the material, this action resulted in substantial confusion when products suddenly failed to meet specification. Another example can be gained from the recent press release from Source One where they stated the leading supplier of tocotrienol standards had a 30% error in their reported purity. I feel that this is a very serious issue that could cause financial harm and legal liability to good companies trying to do the right thing. FDA's position is pretty clear: they expect standards to be properly qualified by valid, scientifically sound methods. FDA puts every standard they get through a whole battery of tests which the majority of companies from my experience (except for USP, NIST and NRC) fail to do. These companies are expecting that the suppliers they purchase standards and botanical reference materials from are doing due diligence which may not be the case. One point that is repeatedly emphasized in the new cGMP regulations is that all responsibility falls on the manufacturer for compliance with GMP regulations. They can't pass the blame to their standard supplier, contract lab or raw material supplier. The FDA holds the manufacturer fully accountable. Litigation and the FTC UCC is another story. However, a vigilant manufacturer can learn what questions to ask and what documentation to obtain when they are purchasing standards and botanical reference materials from suppliers. As a concerned supporter who really cares about the longevity of this industry, I encourage you all to protect yourselves from unqualified suppliers of standards and botanical reference materials. Let the science speak for itself and learn to question everything! If anyone is interested in getting a copy of the article please let me know.

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Comments (3)

Re: Reference Materials and Standards-What is in the Bottle?

By jamesnealk on 6/29/2007 10:51 PM

I just wanted to express my appreciation for the excellent work done in this journal article. It should be mandatory reading for all companies involved in working with botanical dietary supplement ingredients. As an FDA trained botanical microscopist and university instructor in botanical drug identification by HPTLC and microscopy, I have seen an amazing degree of variation in what is called a “voucher specimen.” I consider a botanical reference material something that has been highly characterized through the use of taxonomic keys by a properly trained botanist, taxonomist, or other qualified expert. Even with mounted herbarium specimens that I have paid several hundred dollars for, I received the wrong species. Imagine the damage done by publishing research and building quality control methods in such circumstances. This is a scenario I have seen time and again over the last 15 years.

With the passage of the new Dietary Supplement GMP’s, it seems that “experts” are coming out of the woodwork left and right with botanical reference standards and testing programs that can identify exotic botanical species down to the chemotype level. It reminds me of what happened after the industry exploded from the popularity of St. John’s Wort. Suddenly, every lab had expertise in phytochemistry. The result was a landslide of hack science that damaged the industry. What I see happening now concerns me very much.

An herbarium specimen or voucher specimen is very costly and to obtain one, it must be harvested at the correct time of year in the proper region. Further, one also needs the “material of commerce” which is the plant part used in making the supplement. I will give an example. Many years ago, I obtained a saw palmetto herbarium specimen. This was a palm frond mounted by a botanist indicating the species, harvest date, location, voucher number, etc. and was accompanied by a letter from the expert attesting to its authenticity. It was harvested from the same plant material that the berries were obtained from. These berries were the “material of commerce” and the herbarium specimen was the link that allowed me to assure myself that I had the right berry. I have numerous vouchers all at a cost of several hundred dollars each. While universities have huge herbariums with numerous vouchers, it is very uncommon in the private sector because a collection of even a thousand vouchers purchased from expert botanists would run around $500,000 dollars US and the material of commerce is short lived. What concerns me even more is the number of calls I have received lately from highly respected botanists and chemists in academia enraged that they were sold the wrong species for a research project wasting valuable time and money from companies in our industry.

Each botanical specimen will require unique tests to assure identity. For instance, I can tell if you have saw palmetto by looking at and smelling the whole berry. In a case like this, you could make a good argument for organoleptic testing meeting the identity requirement of the new GMP’s. However, if you are working with powdered plantain, that changes dramatically. I would want to do a TLC test to fingerprint the phytochemicals indicative of authentic plantain. I would also want to do microscopy to confirm that the sample had the correct histological features present. However, that would not be enough. In addition, I would do a Kedde reaction to confirm the absence of lanatosides (cardiac glycosides) and maybe a TLC run for lanatosides. Further, I would want to run additional microscopic studies for the presence of glandular trichomes. Even after all of this, the only valid conclusion that I could come to is that the profile matches the profile for plantain as outlined in whatever reference source I have and that no evidence of adulateration with Digitalis lanata was detected. I could not say that the material is 100 percent pure because I could not tell even after running all these tests.

Then there is Hoodia. My esteemed colleague, Dr. Ikhlas Khan and his team have done an incredible amount of outstanding work on Hoodia species including the isolation and characterization of several oxypregnane glycosides called Hoodigosides. What he found was that he had to completely change the method used in his earlier research to allow for the adequate chromatographic separation of these markers in order to make proper identification of the botanical material. The popular marker P57 is found in more than one Hoodia species. Thus, the HPLC detection of P57, TLC fingerprint and microscopic histology of powdered samples are still not enough in most cases to make a call of a botanical material being pure Hoodia gordonii. At best, you could say that the material contains a Hoodia species.

So, if you are purchasing botanical reference standards, I would urge you to be sure that you are supplied with complete documentation including the location of the herbarium specimen used to authenticate the material. If you are the manufacturer of a product found to contain the wrong species, it is not your contract lab or standard supplier that takes the hit from the FDA. It is you and you alone. The GMP’s are very clear about that. The FDA is not going to allow manufacturers to pass the buck to suppliers, contract labs or chemical standard/reference material suppliers so you better be sure that you educate yourself in full about what you are doing. A reputable company will be very upfront and open about their process and should be willing to supply you with supporting documentation so that you can do your due diligence.

I deeply care about the dietary supplement industry and want it to grow and thrive under the new GMP’s. It has been such a wonderful experience to have spent most of my professional career as a scientist working with an industry full of diverse, talented and unique people who, in most cases, are doing great things. Unfortunately, many people with very good intentions get in over their head because they do not understand the complexities of phytochemistry, taxonomy, botany and related disciplines. These good people are often the victims of companies that either don’t care about what they sell or are too ignorant to understand that what they are doing is far below the standard of peer-reviewed science. Nobody is an expert at everything and that is why taxonomists, botanists, herbal practitioners, chemists and others in this industry must work together as a team to shed light where there is darkness. We all need each other and our cooperative spirit is what makes this industry great and what will allow us to thrive. Congratulations to the Dietary Supplement industry for finally receiving the cGMP’s that you so very much wanted. Let’s use them to show the world that we are an excellent industry of caring, ethical people providing quality products so that consumers can live healthier, more fulfilling lives.

Re: Reference Materials and Standards-What is in the Bottle?

By mroman123 on 7/2/2007 3:27 PM

"Reference standards" are one of the largest sources of variance in results between laboratories. Commercial suppliers of these compounds often have different standards of evidence to assign purity (i.e. one company may use TLC, and another may use HPLC-MS). Most commercial suppliers, however, do not do adequate testing to accurately and reliably assign a purity to the reference standard. As an example, if a company uses HPLC-UV, LC-MS/MS, NMR, water determination by Karl Fischer, and residual solvents by GC-MS to assign a purity, it will tell you nothing about the heavy metal or inorganic salt content of the standard. The product that you are paying $200 for 10 mg could be 50% table salt, but the analytical testing that was performed will not show that. In addition, if only single analyses of each type are performed, there will be no indication of the uncertainty of the assigned purity.

As a result, there is often a great deal of variability in actual purities not only between suppliers, but also between lots from the same suppliers, and sometimes even between vials from the same lot, even though all might come with a COA that states "99.6% purity."

Whenever issuing results for an analysis, it is prudent to indicate the supplier, part number, and lot # of the reference standard used to generate the result.

Re: Reference Materials and Standards-What is in the Bottle?	By BJacobs on 4/20/2008 8:32 AM
I would very much appreciate a copy of your manuscript! This will serve as an important contribution to the field!!