FDA cGMP compliance project update

This week saw an excellent development in the quest to provide open-source resources to the herbal community in our efforts to achieve compliance with FDA cGMP regulations: AHPA (the American Herbal Products Association) has posted hundreds of document templates, including manufacturing record templates, testing method templates and specifications, policy templates for almost anything you could imagine (and more) that might be involved in making an herbal dietary supplement. This is a great resource (thank you Ellen Kahmi, http://www.naturalnurse.com for bringing this to my attention the day it was released). Find it here:

http://ahpa.org/Resources/cGMPSOPTemplates.aspx

As you can see, the list of available documents is quite extensive. It is available for members of AHPA (base-level membership for a small-scale manufacturer is $1,000 per year. AHPA is a fantastic organization. $1,000 is a lot of money).

Another development is that I will no longer be posting updates and documents at this site, but rather at a new dedicated site where you can find all previous information and also future updates. Find it here:

https://sites.google.com/site/gmpopensource/home

Hopefully this will be a more practical way for us to communicate about this. Over the next few weeks, I will be reaching out to folks who have expressed interest in helping, to make them contributors to the site and allow them to edit and add material as they see fit. There are a few items I might suggest putting on our agenda and to-do list for this project:
- live online forum discussion to help us meet, define the work, and agree on goals
- working through explaining the pieces of cGMP compliance (more documents and voice-overs of why they are structured the way they are, and how to customize them for your own business)
- the problem of testing, and its cost: even a testing program that takes random annual samples (which requires some baseline level of confidence in raw materials and in-house manufacturing, and data to support it) still can run hundreds or thousands of dollars, depending on how many products you make
- the lingering uncertainty around defining identity and strength specifications, and testing for those specs, for a multi-botanical herbal dietary supplement.

I'm taking next week off. Stay tuned at https://sites.google.com/site/gmpopensource/home for further updates in the new year.

FDA cGMP project - raw material identity specifications and testing

**NOTE: all the information presented under the "FDA cGMP compliance open source project" is not intended to be legal advice, nor is it in any way guaranteed that my interpretation of the statute and system for compliance is going to satisfy any individual FDA inspector or compliance officer. These pages are a synthesis of my own understanding of the regulations and how to achieve compliance.

When manufacturing any dietary supplement (herbal or otherwise), the guidelines on current good manufacturing practices (cGMPs) require that specifications be established for everything that goes into what you're making. This essentially means that you have to define a few things and set a standard that you find acceptable, and then test the relevant material and record the results of that test. The regulations under 21CFR111 tell us what specifications we need - sort of. Let's take a look.

A great outline of all of 21CFR111 is here:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?CFRPart=111
and, for the details on specifications, see section 111.70:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=111.70

The key pieces are identity (what is it?), purity (for a raw herb, is it all the herb in question? Is there dirt and/or foreign non-herbal matter?), strength and composition (for a raw herb, this is full-strength 100% raw herb), and contamination.
The identity, purity, strength and composition for whole or cut-and-sifted (NOT powders, which require a microscope) can be assessed through organoleptic testing (using sight, smell, feel, and taste) if conducted by a qualified herbalist. The contamination, unfortunately, requires help. This is even if you get a certificate from your vendor telling you that there is an acceptably low level of contamination, if any. This is one of the big pieces that we still have to solve as herbalists: the cost for contamination testing of each batch of raw material can get steep. Is there a way to consolidate results on lots of herbs so all can benefit and/or spread the costs?

Identity specifications are established in an herb monograph, and there should also be a voucher sample of the herb in question, as well as a sample of the cut-and-sifted material if that's how you purchase it. Additionally, details should be included about potential adulterants, if an herb is known to be adulterated (goldenseal and yellowroot for instance). Rejection criteria - meaning, if you find this you mail the herb back to sender - should also be included.
AHPA has begun to collect excellent information on botanical identity, including microscopic identity. You should visit:
http://www.botanicalauthentication.org/index.php/Main_Page
Purity specifications can include details on adulterants, but also a way to assess (and reject if necessary) how much filth and foreign matter is present in a sample.
Contamination specifications include:
- microbiological testing. What's an acceptable total bacteria count? What about yeast and mold? Note that in many cases, bacteria, yeast and mold are a normal part of, say, a fresh berry. Without them there would be no wine. But sometimes there's too much. And certain specific bacteria, like E. coli and salmonella, should never be present.
- heavy metal testing. How much arsenic, mercury, lead, cadmium are in the sample? It's tricky to determine what an acceptable level could be for a raw herb. Additionally, there is good evidence that tincturing actually removes heavy metals from the final product (because most, if there are any, remain in the discarded marc).
- pesticide testing. Our argument so far has been that using certified organic herbs shifts the burden of responsibility to USDA, and that we are not required to test for pesticides. We do use only certified organic herbs. This may or may not be enough - the jury is still out. I'd be curious to hear of other's experience here, especially if there has been pushback from FDA even for those who use certified organic raw material.

AHPA has put out great guidance documents to help define these specifications. For an overview, see:
http://www.ahpa.org/Portals/0/2009/10_0120_Guidance_Policies.pdf
And, for much more details on heavy metals specifically:
http://www.naturalhealthresearch.org/wp-content/uploads/2013/02/09_1214_AHPA_Heavy-Metals-White-Paper-Revised.pdf

The above is good, but the heavy metals specifications refer to daily total maximum intakes, not how much can be in an herb you're planning to use. This is a complex question that has to do with the weigh-to-volume ratio of your tincture(s), the dose, and how much heavy metal is left in the tincture from the original raw herbs. Working backwards from the daily limits, you can make a case for how much should be present in a raw herb. Here is an example of how to make such a case, and includes the final heavy metal limits:
Heavy metals contamination rationale.

Again, the problem isn't necessarily defining the specification, but testing for it. These tests can get quite expensive. There are ways to reduce the amount of testing you do, especially once you have some data to go on - but getting there can be an overwhelming financial burden. We need to find a way to collaborate on these types of tests - to spread the financial burden and somehow, effectively, share results if we want to support small-scale manufacturers.

What follow are a couple of examples: the first is a raw material monograph (the specifications) for Echinacea purpurea root. The second is a specification sheet, where the results of testing are recorded to ensure they comply with the specifications. A voice walk-through is below as well.

Full document .pdf file

Full document .pdf file

mp3 file download

One note: these are "controlled" documents. They must be signed, dated and approved by whomever is in charge of quality control; revision numbers must be advanced if any changes are made; and they should be "secure" (i.e. not easily tampered with or alterable). Filled-out spec sheets must be in hard copy, filled out in ink, and stored. Until this documentation exists, and is signed off at the bottom, you cannot use the herbs for manufacturing and they should be stored in a designated "quarantine" area (blocked off by fencing, walls/doors, or even tape on the floor to distinguish the area from one of active use).

Finally, one cannot necessarily rely on organoleptic testing unless the person conducting the test(s) is qualified to do so. While you don't have to convince me that you know what dry, cut-and-sifted Echinacea purpurea root looks, smells, and tastes like, you will have to convince FDA. Plus, herbalist qualification does raise some interesting questions: could you tell the difference between E. purpurea and E. angustifolia? Perhaps. What about Actaea racemosa and Actaea pachypoda dry, cut-and-sifted rhizome? It's not always so straightforward. Again, AHPA is doing a great job putting together a lot of the specifications and images necessary for herbalists to conduct these tests (see, for instance, the detailed Actaea racemosa monograph), but unless you are a botanist or pharmacognosist with a degree, you will have to prove to FDA that you can competently identify herbs. Essentially, you have to find a way to "test the tester", or qualify the analyst, who is ensuring that the organoleptic specifications are being met. Here are two document that give an example of how one might do this:
Analyst testing method (how we test our testers)
Analyst testing record (where we record the test results)
Ideally, you will build a testing record that shows you can competently identify all the herbs you use. Now, the question remains: how do you know that the sample you're using as a way to certify the herbalist's skill is actually what you think it is? This requires either the purchase of a validated sample, the assistance of a qualified botanist or pharmacognosist, or validation through an external lab test. This can add extra cost. Is there a way for us to centralize this somehow? Could analyst certification be offered at herb conferences?
Any additional training seminars, certificate programs, or herb schools that you can attend (and collect certificates!) serve to bolster your case that you are, indeed, qualified to conduct these tests. Build a strong case, and identity of raw (non-powdered) herbs can be tested using our senses and good reference materials.


So, specifications need to be developed for everything - including packaging and labels - and you have to maintain a record that you checked everything that comes in against those specifications before using material to make any kind of product that will go to the public. This is a big undertaking. In the coming weeks/months we'd like to share as much of what we have as possible. Hopefully these documents can be edited, improved, and custom-tailored to adapt to different individual situations. But the scope of the project has already outgrown this blog: we need a platform that allows for collaborative sharing, posting, and discussion. So next week, I will provide links to a separate website that will hopefully be more interactive and allow us to leverage the excellent experience and advice, as well as offers for help and contributions, that have been coming our way. Thank you for supporting the FDA cGMP open source project and stay tuned!

FDA cGMP project - labels and language

Though not technically part of the regulations that govern good manufacturing practices, product labels, websites, and social media pages and the language they contain are also regulated by FDA and are, unfortunately, a ripe potential target for government agents who enjoy browsing the internet at their desks. Lately, warning letters have been issued just for unapproved website claims (for example, here). Regardless, it makes good sense to start by having compliant packaging and marketing materials: anything else invites scrutiny.


**NOTE: all the information presented under the "FDA cGMP compliance open source project" is not intended to be legal advice, nor is it in any way guaranteed that my interpretation of the statute and system for compliance is going to satisfy any individual FDA inspector or compliance officer. These pages are a synthesis of my own understanding of the regulations and how to achieve compliance.

We'll look at the label itself in a bit. First, what about claims on labels? There are two types: ingredient claims (this much Vitamin C, for instance, or these many calories), and structure/function claims ("supports healthy immunity" and other such language). It's rare that herbalists will need to make nutrient claims - but I've included a label for a product that contains some honey, so you can see how to articulate the carbohydrate count on a label. But structure/function claims are a source of perpetual befuddlement. What can be said? What cannot? Are there code phrases or tricks?

I will start by saying that there really aren't tricks. You can't get away with saying "this statement has not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease" and then making any claim you want. You can't say "traditionally used" in front of any claim you want, and think this exempts the language. You can't get tricky and say things like "useful during the cold and flu season", because colds and flus are diseases, and herbs can't be useful during disease season because "useful" can only mean "medically useful" in this context. You can make a claim that a supplement supports the normal, healthy function of an organ, system, process or function of the physiology, provided those processes and functions are part of the normal, healthy course of life. You can also use language that FDA doesn't understand, or considers meaningless - like "enhancing yin" or "unblocking stagnant liver qi".

This is the tricky part. It really is up to FDA to decide what a normal, healthy course of life looks like and I have to say that, based on my experience, it appears FDA (and/or their medical consultant squad) spends a little too much time sitting at desks on the computer, eating a questionable diet, feeling stressed and not sleeping too well. This is in part because anxiety, tension and stress, occasional heartburn, gas, upset stomach, PMS and insomnia are all considered part of a normal, healthy course of life. But I digress.
Blood-based parameters - like blood sugar, cholesterol, pressure etc... - are fair game as long as it is clear that the herbal product "supports healthy blood sugar levels that are already in a normal range" (emphasis mine, and is required). Anything else would imply disrupted blood levels, which means disease. Certainly can't mention diabetes.
I have found the following document very helpful:
http://www.fda.gov/ohrms/dockets/98fr/010600a.txt
It gives a good background on how we got here (namely, the Dietary Supplement Health and Education Act, or DSHEA), which is interesting to read if you like context. But you can also search the document right in your web browser. Try typing in "heartburn". Or "blood pressure". Or "insomnia". Then, try "potency" (improving sexual potency is not an acceptable claim, but improving sexual performance is - poor performance is apparently part of a normal, healthy course of life).
These searches give you ways to approach herbal actions from an acceptable structure-function perspective, and more importantly, if you spend a little time reading, you can get a good sense of what will be acceptable, and what might get you into trouble. There are some tricks - "occasional" heartburn and sleeplessness are fine, but without that qualifier, they are diseases (though of course this wouldn't work for "occasional" migraines). Best of all, FDA explicitly says "this is acceptable" after a good many statements, and you can use these statements as you see fit. Beyond this, you have to prove that a claim refers to supporting something that happens anyway as part of being a healthy human if you want to use it.
All claims - even mentioning the word "immune" in a product name - must have an asterisk next to them. This asterisk must point to the FDA disclaimer somewhere on your label, which must be enclosed in a hairline box: "These statements have not been evaluated by the Food and Drug Administration. This product is not intended to diagnose, treat, cure or prevent any disease."

These regulations around claims apply to print and internet material, too. Brochures, business cards, shelf talkers and sales sheets, catalogs, websites, and social media pages - even, perhaps, audio and video - must all comply (and must include the FDA disclaimer). You can't control what others post on your sites - but don't "like" or acknowledge them. Testimonials, if not properly worded, aren't acceptable either. Personally, this is a big loss: I remember back in the day herb companies often had some of the best information on herbs, their pharmacology and applications, in their print and web media. Now, you can't even post a study that references one of the herbs you use because it's seen as implying that the herb can actually do what it does in the study.
One way around this is to set up, or ally yourself with, a few personal social media pages and weblogs. You can link to these from your product pages, even if these external sites say outlandish unacceptable things like how herbs prevent heart attacks. Some warn that such sites must be "two links" away from your herbal company's website - I haven't seen this distinction in action yet.

Once you have defined what acceptable claims you want to use (and I do recommend connecting with ahpa.org to find a lawyer to review these, if you have the financial means), you are required to submit them to FDA, just to let them know that you're saying herbs do things, within 30 days of beginning sales of the product. Here's an example of what such a letter might look like, including the address to send it to:

Herb Pharm Liquid Herbal Extract Vein Health Letter.

Furthermore, you are required to have files that substantiate the claims you're making: if, for example, your elderberry syrup says it supports the immune system, you should have a file that references actual research and dosing, and/or traditional sources (such as 19th century texts), pointing to elderberry's effectiveness (you just can't ever share any of that information with the public on your website).

How to build such claim substantiation files? In the near future, I'd love to start sharing some of what we've put together and would welcome anyone else's support in this. Perhaps a shared online repository? To a certain extent, some of the files are customized for a particular formula or extraction - but there is still the possibility for substantial overlap. For now, start at Health Canada (in many ways more enlightened on this particular regulatory topic), where monographs on many plants are included with references that back up a range of claims. Note, however, that most of these claims are unacceptable to FDA - such as Ashwagandha's effect as a sleep aid - but you can rephrase it as "helps with occasional sleeplessness" and use the Health Canada reference as part of your claim substantiation.

http://webprod.hc-sc.gc.ca/nhpid-bdipsn/monosReq.do?lang=eng&monotype=single


Now, we can look at the specifics of label regulations themselves. There are rules for how a food label generally, and a dietary supplement label specifically, must be structured. There are also variations in requirements depending on the label size. And there is a specific exemption: if there are no nutrient claims or structure/function claims on the label, and there are no wholesale sales, and total annual sales are less than $500,000 or there are less than 100,000 units of a product sold, then having a supplement facts label is not required. If you want to sell your products through a store or distributor, this exemption is not an option. It really only applies to herb shops, farmer's markets, and direct-to-consumer sales.
General rules on food labeling, including the details on exemptions (found in subsection (j)) are in the Code of Federal Regulations (CFR), Title 21, Part 101, subpart 9 (abbreviated as 21CFR101.9). Find the whole thing here:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=101.9
Specific rules on dietary supplement labeling are in 21CFR101.36, which is available here:
http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfcfr/CFRSearch.cfm?fr=101.36
I'll go over these regulations while looking at some specific label examples, which makes it much more clear. But a few pieces to note:
- less that 12 square inches on a label allows you to use 4.5 point font. Anything bigger than 40 square inches requires 6 point at a minimum for text, and 8 point at a minimum for the serving size text in the supplements facts box.
- note the requirements for hairlines, lines, and columns in the supplements facts box. There are some good examples included in 21CFR101.36
- list plants by common name and include the part (root, rhizome, leaf, seed, flower, etc...)
- many herb supplements only need a proprietary blend listed, along with a symbol pointing to a footnote that says "% Daily Value not established". If you add honey or other sweeteners, you may need to list the carbohydrates/sugars, and perhaps the calories, per serving (if the amount per serving exceeds 1g of carbohydrates, and/or if it exceeds 5 calories). The website nutritiondata.com gives good carb/sugars counts for various foods (and a whole lot of other stuff, here's an example for honey: http://nutritiondata.self.com/facts/sweets/5568/2). Just remember, if your serving is 2ml, and there's less than 1g of carbohydrates in there, you don't have to list them on the supplements facts panel.

So, with a little of the background information available, let's take a look at some example labels for two different sizes of a dietary supplement that also contains a little honey. Because writing it all out would take too long, here is a voice walk-through identifying all the important pieces of a (in this case liquid) herbal dietary supplement:

And here are the labels: first, a larger size with a complete supplements facts panel.


Next, a small size with a "linear" supplement facts declaration (only for labels smaller than 12 square inches, though you could make a case to use this way if it's under 40 square inches and there's no room for a big panel).





Next week we'll start to talk about the ingredients and packaging that go into making dietary supplements: from herbs and other ingredients, to your labels, bottles, closures and seals. We'll look at specifications and hopefully get to some ideas on testing. Another piece to cover (if we can get to it) is getting to know your vendors and "qualifying" them to help streamline future work. As always, questions and comments are welcome and I will do my best to include your experience in the conversation. Anyone who has had labels vetted by FDA inspection or legal counsel is really encouraged to send examples to guido at urbanmoonshine dot com. Thank you!

FDA cGMP project - overview

**NOTE: all the information presented under the "FDA cGMP compliance open source project" is not intended to be legal advice, nor is it in any way guaranteed that my interpretation of the statute and system for compliance is going to satisfy any individual FDA inspector or compliance officer. These pages are a synthesis of my own understanding of the regulations and how to achieve compliance.

The landscape of FDA compliance may seem vast, and, indeed, it is. I will tell you, however, that it is not as vast as the landscape of human health and disease: it is much easier to understand than medicine and healing are, and certainly easier to learn. If we are to approach this landscape, which includes forms, research papers, logs and checklists, documentation and reference samples, specifications and lab journals, scales and thermometers, and more, I contend that the best way to begin is to do what herbalists do best: start by finding broad patterns, understand intent and intention, and look at the landscape from high above.

Being an herbalist means you can really improve a friend's condition without fully describing the fine details of their pathophysiology: you can observe the state of their tissues, address imbalances using macro-level energetic descriptions, dovetail them with safe herbs, and achieve excellent results. As you gain experience and deepen your study, you add detail and complexity. It can be a similar process - thought much simpler - to understand what goes into FDA compliance. Bringing that understanding into action can be more difficult - but less so if you know the big picture all along. Essentially, complying with regulations isn't a proscribed set of steps - you have to have a, b, and c done in exactly this way. Unfortunately (or fortunately, depending on how you look at it), FDA expects manufacturers to think for themselves within established parameters. So we can't just "copy" something and expect it to work for us (though having examples is really useful). There isn't a "secret formula" to achieve compliance. We've got to understand the patterns and intentions behind the regulations.

If there is a central point to FDA compliance - something akin to the herbalist's understanding that a living being will attempt to nurture and increase life if given the chance - it would be that one must present proof. You can do almost anything if you can present proof. Ask yourself: how do I really know that this is the case? Where's the proof? It isn't that lab tests are what you need to ensure your dandelion tincture is dandelion. You just need proof: an herbalist looking at that tincture, savoring it, shining light on the dropper may be just as good (in fact, like any good sommelier will tell you, the human palate is way better than a machine). If, that is, you can prove the herbalist is competent. Part of why labs are used so often is that it's actually cheaper than to train a competent herbalist. But for those of us who have followed plants from seed to harvest, who have intimate knowledge of how the veins branch in the leaves, how he flowers change when they dry, how the flavor changes with age - identifying plants is a skill woven into our very fabric. We just have to prove it. Do you have a journal where you record your observations of the plants you harvest and use? Having one will improve your skill, but also serve as an important piece of the proof.

When you make and sell an herbal product, there are four key areas that require attention to proof.

First, what goes in to your product? We need to know about everything - from herbs, to bottles, to your chopping surfaces, to labels. It all must be controlled from start to finish: not used until it's proven to be the correct component, secured, sanitized if appropriate, accounted for, and tracked. If you harvested four pounds of Echinacea root, how do you prove it was four pounds? You weighed it? Really? How do you know your scale is accurate? When did you last check? How do you know it's Echinacea? Because you're an herbalist who grew it from seed? Really? Who says? What seeds? 

You get the idea. It may seem daunting, but once you've got the basic pieces together (we can share examples), you don't have to do it again: you calibrate the scale daily with a standardized weight at a standard temperature. You studied herbs for over 10 years - here's the conferences you attended, the field work you did, the teachers you studied with and when, and furthermore, you conduct blind taste tests on yourself a few times a year and you're consistently accurate. These are all examples, but you get the sense of the work. Lay a solid foundation, and you can get to making products confident that what you're using is what you think you're using - and you can prove it to FDA.

Next, how is the product made? If you're going to build a cabinet, you won't just go get some wood from the lumberyard, make some cuts, and put it together. Hopefully, you will make a plan first. Ideally, the plan will cover everything you need to make that cabinet: materials, cuts, tolerances, specialized processes. Making herbal products requires a plan, too: to ensure consistency of execution and also to prove that product consistency exists, and that no errors were made. How do you know this gallon jar of Echinacea tincture, made from 2 of your 4 pounds, is the same as the next gallon jar made with the other two pounds? There are some specific requirements here, mostly related to the possibility of human error. For example, one part of the plan should be to gather all your ingredients first, then mix them. This may seem obvious, but let me give you an example: when I was first starting with tincture making, I'd want, say, a pint of 50% alcohol. So I'd take a pint-sized measuring cup, measure out 8oz of grain alcohol (let's assume, just for simplicity, that grain is 100% alcohol), then pour water into the alcohol until I got to 16oz, and there you have it. Do you see a problem with this? If you do, you are correct. We'll need to cover the checkpoints necessary to prove that the product is made consistently and accurately. 

Then, what is the product - and what is it not? We have to describe and define what our tinctures are so that we can check to make sure, once they're pressed and ready to go, that they turned out right. We have to prove that the Echinacea tincture actually is Echinacea tincture. If you've ever tasted Echinacea tincture, you might think I'm silly. But try watering it down 10%. Come back a few days later and taste it again. Is it Echinacea tincture? How do you know? You need some kind of reference standard. We'll cover ways to make one, and in our experience with FDA, this way works - without expensive lab tests. Part of the solution relies on covering your bases in the two previous steps. 

But you will also need to define what your product is not: not contaminated with bacteria, not loaded with heavy metals, not laced with pesticides. These are harder questions to answer, and may require a lab. One of the big questions I have is how to create a way to reduce these costs for small-scale herbalists. We know some things that don't work (for example, believe it or not, FDA doesn't buy the argument that 60% alcohol basically kills all bacteria in a tincture. At least not in blanket fashion. Has anyone made such an argument successfully? I'd love to know). 

Finally, where does your product go? You need to establish a way to trace specific lots, with a granularity of each bottling run, to where they go: what stores, what customers. If you bottled half your pressed Echinacea tincture in 2oz dropper bottles on one day, and the other half a week later, they should have different lot identifiers. FDA wants you to be able to account for each and every bottle. Records of bottling = sold product + what's still on the shelf (no more, no less). You sold some product? Really? To whom? Prove it.

For many businesses, this will be part of an already-existing inventory control and invoicing system. But you can do it using modern e-commerce tools (like Square) too, as long as you enter the lot of the product for each sale. Part of what FDA inspections involve is a mock recall: they'll pick a product and a lot, and ask where every single one went.

The areas where we need proof are, to the best of my understanding, described above. It's pretty broad, but if you keep those four key areas in your mind, you will stay mindful of the intention behind the current good manufacturing practices (cGMPs). Once we start getting into specifics, don't lose sight of those overarching areas of proof that are needed. 

But before that, there is an important area which, as has been suggested, has well-defined guidelines (mostly) and just requires following rules: labeling and language. As David said, "Labels are your brand's face to the world". And, increasingly, so is your website and social media presence. Compliance on this front can be easily achieved, because the rules are fairly clear, especially if you refrain from saying your product does anything at all. Since that's pretty ridiculous, there is a law that says we can make "structure/function" claims about our herbal dietary supplements. What this means is less clear - but there are good resources available to help. Next week I'd like to start here: what does a label need? what is a supplement facts panel and how must it be formatted? what kind of language can go on a label / website / facebook page? If folks have experience and resources, please share them next week and I will add them to the page for everyone to reference. I will start out with some detailed examples (vetted as compliant and FDA-tested), links to the relevant pieces of the statute, and a voice walk-through for both to help navigate the examples. 

Thanks for reading, feedback always welcome, stay tuned.

FDA cGMP compliance open source project

Our strength as herbalists is that we come together. We share processing tips and secret harvest spots (sometimes - depending on who's asking), discuss difficult cases, and generally help each other learn. This has been evident to me all the way from herbalist pot-lucks to the biggest herb conferences. Now I believe it is time for us to come together on another critical issue: the modern regulatory environment, enforced by the FDA, in which we find ourselves.
At Urban Moonshine (we make bitters and other tinctures and blends), I can't say we've come to a complete understanding with FDA. The issue of how to identify a liquid formula made from multiple herbs remains. But we have been through every step along the way, and have discovered successful strategies that FDA agrees are valid, and that rely on traditional methods for evaluating and identifying plants - the way herbalists have always done it. These strategies have been tested through multiple inspections. And now it's time for us to share them, share templates of the paperwork, share the research that justifies the specifications we've developed, and help explain what the regulations are, what FDA wants, and how to get there. Not because we've got all the answers, but because we want to open the conversation and create a forum where small-scale producers can get actual news they can use - not just copies of the rules, but actual examples in action. If we can have an ongoing conversation and herbalists across the country can share their collective wisdom, I know we'll have the tools to support anyone who wants to make tinctures for sale in their local communities or across the country.
I won't lie - this is a complicated task, and there are a lot of moving pieces. It's not something you can understand over a weekend and implement with a few days' work. This complexity may have deterred a lot of you, and in the future, may make it impossible for some to keep their heart-centered, small-scale herbal products on the market. FDA welcomes consolidation in the industry - hoping that herbal medicine will become concentrated in the hands of a few, and thus easier to control, easier to oversee.

**NOTE: all the information presented under the "FDA cGMP compliance open source project" is not intended to be legal advice, nor is it in any way guaranteed that my interpretation of the statute and system for compliance is going to satisfy any individual FDA inspector or compliance officer. These pages are a synthesis of my own understanding of the regulations and how to achieve compliance.

We reject the idea that our medicines can only be made by large-scale manufacturers. Despite the pressures today, there is a safe way forward for the community herbalist to make medicine, to  keep this vital and direct link between plant and health alive.

First, we must show that we herbalists – not physicians, not research scientists, not machines, but herbalists – understand the plants we use, and know the intimate details of their growth, their smell, their taste, their essence. We must show how herbalists have a clear, practical and safe way of successfully matching plants with people. Second, we must support a model that relies on customized, individualized medicine making for the local community: a practitioner-based, rather than product-based, economic relationship that focuses on plants, not pills; that encourages client self-care and self-resilience, rather than product-based dependence. And  third, we must reach out to our partners in all fields, to weave green tendrils into places where they’ve all too long been absent: in the halls of medicine, in the offices of urban planning, in the minds of FDA compliance officers, in the backyards of clients everywhere. 

So starting today, we are committing to unfold an ongoing open-source project to achieve FDA compliance for small-scale producers. Every Wednesday I will post information here, including some audio recordings, starting with an overview of the regulations in layperson's terms and a clarification of what FDA is after, then progressing through the moving pieces from documentation to batch records, all the while providing specific examples of documents that have worked for us and helping to tailor them to your needs. This is starting today, and will continue for as long as it takes. I urge you to take part in the conversation: post comments, questions, concerns, and examples. Ask for more detail, ask why, not just how. We will do our best to answer. But ultimately, we are doing this because everyone involved will get stronger as a result. Our collective experience, once open-sourced, will home in on amazing solutions with the ruthless efficiency of nature. This will help Urban Moonshine as much as it will help everyone else.

Posted below find an outline of the curriculum you can expect. Check back here in a week for our first installment and an overview of the compliance landscape. Contact us if you want to help. But before you go further, I ask you to please consider the idea that this could be done more efficiently than blog posts, uploaded documents, and audio recordings. We are trying to build a fully-interactive online classroom for just this type of conversation - where you can be present, ask questions and get answers in real time, and ensure this open-source process is a two-way street. In fact, we need you here contributing: how do you make medicine? How can we make FDA compliance work for you? It's going to be a lot less effective for this to just be an exposition of information - we all need to know what your experience looks like so we can build a truly resilient and adaptable compliance model for actual herbalists. 

This endeavor needs a lot of infrastructure, and we can't afford to do it alone. From fit-up costs for the space, to AV and telepresence equipment, we are relying on your help to make this a rich, interactive process. There will be a lot of other good stuff along the way, too - but what excites me most is the opportunity to create an open-source compliance conversation that happens every week, with intensive on-site experiences as required, and is available free of charge to anyone who wants to join up. But as you know, nothing is actually free. So please consider supporting Railyard - our herb center project. Hiring consultants for FDA compliance can cost thousands of dollars - even a weekend workshop can cost hundreds. If everyone from a group of engaged herbalists who want to maintain control over their own medicine-making contributed even half that much to the project, we can make Railyard happen. Think about it, and I hope to see you next week.

https://www.kickstarter.com/projects/2032475629/railyard-herbal-apothecary-classroom-clinic

Tentative curriculum (we can customize it together):

Intro to federal regulations

A detailed breakdown of the federal regulations under CFR 21 part 111 (good manufacturing practices), part 101 (labeling requirements), and parts 174-186 (food contact surfaces and packaging requirements) will give the us the tools to critically evaluate a sound master manufacturing record, compliant dietary supplement label, and scientifically valid testing regime.


Herbal Product Manufacturing

The details involved in making a range of herbal products: research, formulation, safety considerations, process control steps required for compliance (FDA cGMPs), extraction, dosage forms, considerations of large-scale operations, packaging supplies.


Facilities and Equipment

We will become familiar both with the basic tools needed for manufacturing and larger-scale equipment such as floor scales, macerating vessels, presses. Maintenance and calibration requirements and tracking.


Records and Paperwork

We will cover the recordkeeping methodology for maintaining a cGMP compliant manufacturing operation, based on requirements from CFR 21.111, and grounded in specific examples currently in use. We will become familiar with creating: master manufacturing records and their associated batch production records; specification sheets for raw, in-process, and finished products as well as eccipients, solvents, and packaging materials; and valid testing methods and documentation.


Marketing, Sales, and DSHEA-compliant language

We will cover design and marketing concepts and suggestions, as well as thoroughly review what constitutes compliant language under DSHEA (regarding promotional material, labels, social media and websites, video, and product trainings).


Quality Control Laboratory

We will become thoroughly familiar with the requirements for identity testing under CFR 21.111, be able to access and compile relevant resources to aid in identity testing (voucher specimens, e.g.), and understand how to contract with third-party laboratories for identity, microbiological, heavy metal, pesticide and herbicide contamination testing.


Orientation to Industry

We will familiarize ourselves with the resources and connections in national professional organizations for the herbal products industry, such as AHPA, as well as legal and consultant resources that might prove useful. Additionally, we will talk about the requirements and practicalities of launching an herbal product: from interfacing with large retailers such as Whole Foods Market, to making barcodes for products, and more.

Herbal bitters: their role in appetite, blood glucose management, and obesity

I am excited to be traveling to the annual American Herbalists' Guild symposium. I'll be presenting a few classes, but below are the notes for a review of the recent research on herbal bitters. Lots of interesting material has come out in the last few years to improve our understanding of how these medicinal plants work in our physiology. I include some practical clinical observations and implications as well.

Summary: Bitter herbs have a well-deserved reputation as digestive aids in most systems of traditional medicine, and in many systems of cuisine. The ability of bitters to support balanced secretion and motility, especially in the gastric phase of digestion, relies on a few important mechanisms that are mediated through taste receptors (T2R family) and involve neuronal, hormonal, and vascular effectors. New research is uncovering additional interesting facts about bitter tasting herbs: first, not all bitter flavors are alike, and a certain degree of variability exists in their effects and spheres of action. Second, additional mechanisms involving adipose tissue, inflammatory mediators, the microbiome, and hepatic glucose balance reinforce the idea that certain bitter herbs may be one of the best strategies for the management of blood sugar and lipid imbalances, the regulation of appetite, and the reversal of the metabolic syndrome.

Background: bitter taste receptors: traditional and modern understanding

The current understanding of our ability to sense taste transcends the classical notions that specific areas on the tongue correspond to specific flavors, or that taste perception is indeed localized to the tongue. Wolfgang Meyerhof studies molecular genetics at the German Institute of Human Nutrition and has provided extensive research into the structure, coding sequences, and function of bitter taste receptors (TAS2Rs, aka T2Rs, a family of G-protein coupled receptors). Some interesting points include the facts that T2Rs present numerous different isoforms, able to sense over 100 different bitter tastants and their combinations [Ref: Meyerhof W, Batram C, Kuhn C, Brockhoff A, Chudoba E, Bufe B, Appendino G, Behrens M. 2010 The molecular receptive ranges of human TAS2R bitter taste receptors. Chemical Senses. 35(2):157-70]; they relay information from the tongue to the nucleus tractus solitarius (medulla) and from there to the hypothalamus using proteins such as alpha-gustducin; and participate in parasympathetic activities such as increased oral and gastric secretions [Ref: Meyerhof, Wolfgang, et al. "Human bitter taste perception." Chemical Senses30.suppl 1 (2005): i14-i15.] More recent research by Meyerhof and others indicates that, unlike most stimulus/receptor pairs in human physiology, the expression of T2Rs increases (to a point) the more stimulus is presented: that is, the more we taste bitter, the more we are able to experience its effects [Ref: Behrens M, Meyerhof W. Bitter taste receptors and human bitter taste perception. Cell Mol Life Sci. 2006 Jul;63(13):1501-9.] What we may, in fact, be noticing is that the human physiology _under_expresses T2Rs until an adequate amount of bitter stimulus is present, at which point a "normal" level of expression is achieved.

Perhaps more interestingly when we consider the inflammatory nature of chronic disease, especially the metabolic syndrome, emerging research is indicating that high levels of pro-inflammatory compounds also serve to _over_express T2Rs, leading to a highly aversive response to even small amounts of the bitter flavor [Ref: Feng, Pu, et al. "Regulation of bitter taste responses by tumor necrosis factor." Brain, behavior, and immunity (2015).] Taste-sensitive cells throughout the body have highly tuned TNF receptors (tumor necrosis factor, a pro-inflammatory compound).
Reducing inflammatory load seems to reduce bitter taste receptor expression, which is of interest when we consider that the effects of phytochemicals associated with bitter taste often are anti-inflammatory.

The neuronal feedback elicited by T2R stimulation (via cranial nerves VII-facial, IX-glossopharyngeal and X-vagus) helps control the cephalic and gastric phases of digestion, coordinating secretion and motility by increasing the former and decreasing the latter. This process has been extensively studied and is well-reviewed by Catia Sternini [Ref: Sternini, Catia. "Taste receptors in the gastrointestinal tract. IV. Functional implications of bitter taste receptors in gastrointestinal chemosensing." American Journal of Physiology-Gastrointestinal and Liver Physiology 292.2 (2007): G457-G461.] The net result is improved molecular breakdown of macronutrients in the chyme that enters the intestinal phase of digestion, as well as slower delivery of those digested products. This underlies the traditional indications for digestive bitters: dyspepsia, indigestion and reflux, gas and bloating. But the slower delivery of metabolized carbohydrates to the small intestine also has a role to play in post-prandial (after-meal) glycemia.

It has been clear for some time that T2R stimulation modulates levels of hormones associated with appetite: ghrelin, a hunger hormone, increases at first. But reduced gastric motility leads to a feeling of fullness, and this, coupled with increased levels of hormones associated with satiety (fullness) such as peptide YY (PYY) and glucagon-like-protein 1 (GLP-1), leads to less caloric intake overall [Ref: Janssen, S. et al. Bitter taste receptors and α‑gustducin regulate the secretion of ghrelin with functional effects on food intake and gastric emptying. Proc. Natl Acad. Sci. USA 108, 2094–2099 (2011).] The modulation of these hormones was long thought to be connected to neuronal reflexes, but emerging research shows that the taste cells themselves function as enteroendocrine cells, are present throughout the GI tract, and secrete appreciable levels of their own hormones into the gastrointestinal circulation. Bitter-tasting substances can harness these enteroendocrine cells and contribute to local secretions that affect absorption, appetite, and the metabolism of fat and carbohydrates [Ref: Posovszky C, Wabitsch M, Regulation of Appetite, Satiation, and Body Weight by Enteroendocrine Cells. Part 1: Characteristics of Enteroendocrine Cells and Their Capability of Weight Regulation. Horm Res Paediatr 2015;83:1-10] and [Ref: Palatini, Kimberly, et al. "Diverse Classes of Bitter Phytochemicals Modulate Carbohydrate Metabolism and Immune Responses through Gastrointestinal Bitter Taste Receptors." The FASEB Journal 29.1 Supplement (2015): 405-5.] Thus, bitters may act directly as endocrine triggers, not requiring intervention by the central nervous system.

Another fascinating result of experimental research underscores yet another effect of herbal bitters. A recent review article by Julie Whitehouse and others [Ref: McMullen, Michael K., Julie M. Whitehouse, and Anthony Towell. "Bitters: Time for a New Paradigm." Evidence-Based Complementary and Alternative Medicine 2015 (2015).], lends evidence to the hypothesis that certain bitters (particularly the more strongly-flavored, classic "eupeptic" herbs gentian and wormwood) increase blood flow to the GI tract. This post-prandial hyperemia is achieved, interestingly, via peripheral vasoconstriction and localized (mediated by enteroendocrine cells again) vasodilation. The overall shifting of circulatory volume can act as a negative cardiac chronotrope and inotrope (reducing frequency and strength of heart muscle contractions), and is most likely the reason (rather than increased tone along the vagus nerve) why this phenomenon has been observed after the consumption of bitters. Practically speaking, this suggests that herbal bitters should include at least one of these classic "eupeptics" for maximal effect - for not all bitter tastants elicit the same effects, and not all reduce ingestion of calories equally, as Lindsay Schier observed [Ref: Schier, Lindsey A., Terry L. Davidson, and Terry L. Powley. "Ongoing ingestive behavior is rapidly suppressed by a preabsorptive, intestinal “bitter taste” cue."American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 301.5 (2011): R1557-R1568.]. Additionally, Whitehouse notes that the vascular shift is almost instantaneous (within 5 minutes) after T2Rs in the tongue are stimulated by strong bitter flavors. This implies that one can take bitters before, during, or even after a meal and that the effects can still be beneficial (consuming them 10-15 minutes before eating is not necessary).

Clinical implications: Appetite, glycemia, lipidemia, hypertension and the metabolic syndrome

It appears that our ability to detect and respond to bitter tastants such as those found in bitter herbs is variable, and connected to the internal and external environment. This is the first step in realizing their therapeutic potential: as we age, the expression of T2Rs decreases naturally, and sometimes (in the absence of any bitter stimulus) appears to decrease beyond "normal" expression. This "normal" level can, however, be restored by applying regular bitter taste stimuli. The "bitter deficiency syndrome" hypothesized by James Green in The Male Herbal (J. Green, 2007) has indeed been documented. Women [Ref: Feeney E, O'Brien S, Scannell A, Markey A, Gibney ER. 2011 Genetic variation in taste
perception: does it have a role in healthy eating? Proceedings of the Nutritional Society.
70(1):135-43.] and children [Ref: Negri, Rossella, et al. "Taste perception and food choices." Journal of pediatric gastroenterology and nutrition 54.5 (2012): 624-629.] have much lower levels of obesity when they perceive higher levels of bitterness. Additionally, individuals with high bitter sensitivity have improved blood glucose control, as extensively investigated by Cedrick Dotson at the University of Florida [Ref: Dotson, Cedrick D., et al. "Bitter taste receptors influence glucose homeostasis." PloS one 3.12 (2008).].

The intersection between bitters and inflammation is of particular interest, as is the potential for a post-prandial GI hyperemia (and a resultant reduced load on the heart and arterial system). First, a strong aversive response to bitterness by an individual who has little experience with the flavor may be indicative of a high background level of pro-inflammatory compounds such as TNF. As the aversion decreases, one could expect that the cholagogue, GI anti-inflammatory, hepatic "cooling" effect might be contributing to reduced inflammation (an interesting balance point between increased expression through T2R stimulation and decreased expression via reduced TNF). Second, reduced inflammation plus reduced cardiovascular load and stress are essential components to any therapy designed to address the metabolic syndrome - and through a wide range of mechanisms, bitters appear to do just that. The connection between the bitter flavor and the heart in some traditional healing systems is of note here, as well. Kimberly Palatini's research, mentioned above, suggests that bitters modulate immune responses in the GI tract and in the physiology overall - while balancing and regulating every aspect of carbohydrate absorption and metabolism, increasing glucose tolerance and insulin sensitivity. Of course, improved insulin sensitivity is a direct consequence of reducing high levels of pro-inflammatory compounds: TNF, as well as series-2 prostaglandins, have all been linked to insulin resistance.

Regulation of appetite, leading to the epidemiologic results observed (lower obesity rates), occurs by a variety of mechanisms. The first is related to motility: through cranial nerve feedback, bitters delay gastric emptying leading to a more rapid sensation of fullness. But just as importantly, wide-ranging effects on satiety, appetite, and carbohydrate metabolism, storage and processing are mediated through enteroendocrine cells - which turn out to be sophisticated "tastebuds" with chemoreceptors on the luminal side and the ability to secrete hormones on the basolateral side. T2Rs are found on P/D cells in the stomach, which secrete hormones involved in fat metabolism and insulin sensitivity (increasing both); on I cells in the duodenum which reduce food intake and stimulate CCK; and on the all-important L cells in the small and large intestines, which secrete PYY (satiety) and GLP-1 (insulin sensitivity) [Ref: Posovszky, Carsten, and Martin Wabitsch. "Regulation of appetite, satiation, and body weight by enteroendocrine cells. Part 1: characteristics of enteroendocrine cells and their capability of weight regulation." Hormone Research in Paediatrics 83.1 (2015): 1-10.]. The recent research and potential of bitter tastants in regulating appetite, obesity and the metabolic syndrome are well-reviewed by Sarah Calvo and Josephine Egan in Nature Reviews [Ref: Calvo, Sara Santa-Cruz, and Josephine M. Egan. "The endocrinology of taste receptors." Nature Reviews Endocrinology 11.4 (2015): 213-227.].

And while bitters have important effects on preventing (and perhaps treating) insulin resistance and diabetes, as we have seen from the mechanisms above, I have also seen them correct episodes of transient, non-emergent hypoglycemia on many occasions. Since hypoglycemia in a non-insulin-dependent patient may actually be evidence of disregulated glucose homeostasis and metabolism (a consequence of insulin over-secretion earlier), this does not come as a surprise. Another mechanism whereby bitters correct transient hypoglycemia may involve "tricking" the hypothalamus into believing food is being consumed. This effect may seem like a simple novelty, but it becomes very clinically relevant when you consider the intense sugar cravings experienced during these episodes. If we had a tool to trick the hypothalamus into believing the craving had been satisfied, our patients could make more rational judgements for nutrition (nuts or other sources of fat and protein). Bitters can provide just such a tool.

T2R receptors, and enteroendocrine G-protein-coupled receptors in general, are receiving sustained attention as potential targets for reversing insulin resistance. Exciting research is coming out of Cedrick Dotson's office (mentioned above), who is stimulating T2R receptors with bitter tastants and comparing the insulin-sensitizing effects to the opposite effects found by stimulating sweet taste receptors (T1Rs) [Ref: Dotson CD, Vigues S, Steinle NI, Munger SD. T1R and T2R receptors: the modulation of incretin hormones and potential targets for the treatment of type 2 diabetes mellitus. Curr Opin Investig Drugs 2010; 11: 447–454.].

Finally, many bitters (especially the more "nutritive" bitters, such as dandelion, chicory, elecampane, angelica and burdock) possess appreciable quantities of pre-biotic starches and can deliver these important nutrients when consumed at clinically relevant doses. Oligosaccharides such as inulin can have useful regulatory effects on bowel function, and over time contribute to lower blood glucose, lower lipid levels, and better satiety [Ref: Nishimura, Mie, et al. "Effects of the extract from roasted chicory (Cichorium intybus L.) root containing inulin-type fructans on blood glucose, lipid metabolism, and fecal properties." Journal of Traditional and Complementary Medicine (2015).]. This may be in part due to mechanical effects (such as an osmotic laxative effect), but may also be due to changes in enteroendocrine cell hormone production associated with a shift in microbial populations. A fascinating study by Patrice Cani hinted at just this type of effect in a small (n=10) group [Ref: Cani, Patrice D., et al. "Gut microbiota fermentation of prebiotics increases satietogenic and incretin gut peptide production with consequences for appetite sensation and glucose response after a meal." The American journal of clinical nutrition 90.5 (2009): 1236-1243.] As Steven Abrams noted, this effect is best observed with long-term, habitual use: prebiotics, when combined with calcium (see dandelion root), reduce body mass index better than a placebo control (n=96, one year)[Ref: Abrams, Steven A., et al. "Effect of prebiotic supplementation and calcium intake on body mass index." The Journal of Pediatrics 151.3 (2007): 293-298.].

Conclusion: The digestive-enhancing effects of bitters are well documented, but may be just the beginning of what these traditional preparations have to offer. When consumed in a formula that includes both "eupeptic", strong bitters such as gentian and wormwood, and "nutritive" bitters rich in pre-biotic starches, and taken habitually in material doses, they exert clinically relevant effects on the metabolic syndrome. Appetite, carbohydrate and lipid metabolism all are regulated. Inflammation and cardiovascular load are reduced. Bitters accomplish this through a variety of mechanisms, including neuronal, endocrine, immunologic, and vascular. They most likely need not be consumed too far ahead of a meal, but at any point before, during, or after, and at relatively high doses for the most substantial effects. Given the resurgence of interest in these traditional preparations from those well-versed in the beverage alcohol and cocktail world, we as herbalists may have at our disposal a powerful, flavorful tool for addressing obesity and the metabolic syndrome - one our patients can relate to, and easily incorporate into their lives as a daily habit.

Plant saponins

This is the transcript of a talk I gave recently (at the Traditions herb conference in New Mexico), and focuses specifically on a class of plant chemicals: the saponins. However, it is also a great example of how plant chemistry, in general, works: "promiscuous" phytochemicals (as Chatterjee describes them) finding effects in multiple areas of the body, and being affected by the body in turn. This is the beauty of herbal medicine: the context matters as much as the chemical does. No wonder we obsess about "constitutions", "energetics", and other systems-based ways of describing phytohominid interactions.

We are moving away from the idea that isolated, targeted chemicals – be they steroids, antibiotics, or other agents active at specific receptor sites in the human body – are the only way (or even the most efficient way) to achieve health-promoting effects.  This is progress. But herbalism has more to offer to the field of medicine than simple polypharmacy: medicinal plants and their chemical cocktails don’t just act on the system, the way a drug might, they interact with it. This means that, when taken habitually the way most herbal prescriptions are, herbs enmesh themselves into our tissues and processes, and their effects have as much to do with what the body does to the herbs as with what the herbs do to the body. Plant saponins are perhaps the best example of this, acting on every level from the formula to the internal organs and everything in between, changing their conformation and altering their behavior as they move through the physiology and interact with its denizens. If we can understand how a human being and a cocktail of botanical saponins relate to one another, then we don’t just open a door to new formulation tricks and pharmacodynamic mechanisms – we get a visceral sense of how truly non-static herbal chemistry is, how it flows and changes, how different contexts affect it in different ways. And this may be the most important piece.

What is a saponin?

In its simplest form, these chemicals consist of a water-loving (hydrophilic) chunk attached to an oil-loving (hydrophobic) chunk. Often, the hydrophilic piece is a sugar molecule, or perhaps a short chain of sugar molecules, and there can be more than one chain on each saponin. The hydrophobic side is usually a hydrocarbon – either a net of carbon rings (triterpenoid) or a steroid-like structure. But since one piece of the molecule mixes well with water and the other doesn’t, saponins (as the name implies) can have noticeable soap-like effects, forming foams and acting as cleansers (soapwort, Saponaria, has long been prized as an easy and abundant botanical detergent).

The basic test for saponins in a plant is easy. Make a strong infusion (leaves) or decoction (roots/barks) of the plant in question. Strain into a 250ml graduated cylinder, and cool. Shake it vigorously for one minute. If a honeycomb-shaped bubble lattice at least 2cm (a little less than 1 inch) persists in the cylinder for ten minutes, you can be positive that the plant is rich in saponins.

Have you ever tasted soap? You may not have. It is quite bitter, eliciting the typical aversive responses of moderate-to-strong bitter flavors. Saponins, with a few exceptions (like licorice), are generally just as bitter. Their flavor is an important part of their medicinal effects, especially early on in their journey into the human physiology.

It is still a matter of debate as to why plants produce these molecules. Some believe they act as browsing deterrents, because of their bitterness. Others have documented antifungal and antibacterial qualities which may help protect plants from infection. Still others hypothesize that the hydrophobic backbone serves as a sort of “ferry” for the sugar molecules, allowing them to cross barriers they normally couldn’t. I suspect that all these stories are true, at least in some part.

The physics of saponins in water solutions

The foam you see when shaking a cup of licorice tea is only the most macroscopic part of the picture. Inside the cup, the soap-like molecules are arranging themselves into interesting little “bubbles”, known as micelles, with the hydrophilic sugar tails sticking out into the water and the hydrophobic backbones clustering together in the middle of the bubble. This is quite interesting in and of itself, as we will see, but imagine for a moment if there were other molecules in the tea – say, for instance, that you had added some propolis tincture to really help with your client’s bronchial cough – that weren’t very water-soluble. If you’ve ever tried adding a dropper of propolis tincture to a glass of water, you’ll know that the resins it contains immediately separate from the solution, turning the glass cloudy and leaving a ring of sticky material behind. If you add that same dropper to a strong, foamy licorice decoction and shake it up quickly, the effect is much less pronounced: the hydrophobic resins are trapped inside the saponin micelles, mixing with the hydrophobic backbones, and stay in solution much better. This effect is known as emulsification.

These two effects – the foaming, and the emulsification – have numerous practical applications, and you don’t need a lot of saponin to achieve them. For instance, soft drink manufacturers add saponins to their products to improve the quality and persistence of the foam “head” [Ref: A.J. Mitchell, Formulation and Production of Carbonated Soft Drinks]. I favor a combination of hawthorn, gotu kola, and turmeric for chronic ligament and connective tissue injury, and for a long time formulated this tincture blend with two parts hawthorn and turmeric, and one part gotu kola. But the turmeric tincture, extracted at a much higher percentage of alcohol, would always separate, sometimes clogging the dropper, once it got diluted by the other two and all its hydrophobic constituents fell out of solution. The problem was solved by adding horse chestnut tincture, from a saponin-rich seed,  to the mix (one part out of five). The curcuminoids stayed in solution, no more clogging, and horsechestnut’s anti-inflammatory power helped make the formula even more effective.

The British Pharmaceutical Codex recommends a ratio of 1 part Quillaja tincture (the soapbark tree, from Chile) to 8 parts resins or fatty acids to achieve an effective emulsion. This highlights the effectiveness, even at low concentration, of saponins as blending agents.

The emulsifying, blending quality of plant saponins in a multi-constituent herbal formula, especially if it contains high- and low-alcohol tinctures mixed together, is really useful. And it may underlie the traditional wisdom of using plants like licorice as “harmonizers” and “binders” in the formula: not only does the pleasant flavor help in compliance, but the physics of the saponins in solution ensures that all constituents remain equally suspended in the blend – in harmony.

Act I – the gastric phase of digestion

First off, taste. The activity of saponin-rich plants like yucca, fenugreek, and even ginseng begins with their ability to stimulate bitter taste receptors – soap-like, after all. From here you get many of the benefits of bitter tastants, and these actions are reinforced once the saponins reach the stomach and duodenum: secretions increase, movement of smooth muscle in the gut becomes less spasmodic and better synchronized, valves close up. This may be part of the reason why so many saponin-rich plants (again, with the exception of licorice) are good at controlling blood sugar spikes: the food we eat doesn’t get to the intestinal phase as quickly, so it doesn’t flood the bloodstream with glucose.

Another interesting topical effect of saponins relies on the intimate connection between the mucous membrane of the GI tract and the respiratory system. Pick your saponin-rich herb: licorice, Senega snake root, yucca root, Platycodon, fenugreek – almost all have at least some degree of expectorant activity. This is probably due to what Simon Mills calls “acupharmacology” – the fact that our gut lining is connected to other tissues in the body via nerve fibers, particularly the vagus nerve, allows a slight irritation to affect those other tissues by reflex. So saponins encourage the upward movement of material from the lungs by slightly irritating the stomach lining with their soap-like quality.

Yet another effect relies on the physical properties of saponin micelles. When bile, which contains appreciable quantities of cholesterol, is released into the duodenum, some of the hydrophobic cholesterol is trapped in the micelles. It is then excreted at higher levels in the stool, instead of being re-absorbed and circulated in the blood. There has been a lot of animal research confirming this mechanism [Ref: Sautier, C., et al. "Effects of soy protein and saponins on serum, tissue and feces steroids in rat." Atherosclerosis 34.3 (1979): 233-241], but it also helps explain the cholesterol-lowering effect of ginseng saponins [Ref: Kim, Seung-Hwan, and Kyung-Shin Park. "Effects of Panax ginseng extract on lipid metabolism in humans." Pharmacological Research 48.5 (2003): 511-513.]

At this point, the molecules are still very similar to what they were in your tea or tincture. But once they enter the duodenum and start to meet pancreatic amylases (starch-digesting enzymes) and eventually gut flora, things start to get interesting.

Act II – the intestinal phase of digestion

The entire GI tract is a sophisticated chemosensory organ – meaning, it’s really good at tasting, and not just the tongue. While bitter taste receptors persist throughout the gut, you also start to see lots of lymphatic tissue associated with the mucous membrane once you get past the stomach and its high-acid environment. In these areas, immune cells proliferate and sample the contents of the food we eat, all the while interacting with members of the microbiome. It’s a deep and rich conversation down there, and we are just barely beginning to understand the language. One thing that seems clear is that many of the signals that travel back and forth are expressed in sugar chains, or chains of sugar, fat, and protein – because that’s  what is found on the outside of most viruses and bacteria (with some exceptions, like the cyst form of Borrellia, the Lyme disease spirochete, which is naked can thereby evade immune detection). What is so interesting is that the saponin micelle, with its core of hydrophobic molecules and all the little sugars sticking out, looks a lot like a small microbe. Couple this with the fact that it’s never just one kind of saponin, but the sugar chain shapes and sizes vary dramatically (ginseng, for example, has over 100 [Ref: Shin, Byong-Kyu, Sung Won Kwon, and Jeong Hill Park. "Chemical diversity of ginseng saponins from Panax ginseng." Journal of Ginseng Research (2015).]), and you have the potential for a very fascinating little micelle to interact with the microbiome and the immune cells in the gut’s lymphatic tissue. Plant saponins are one of the most powerful ways for the vegetable kingdom to participate in the immunologic conversation that takes place inside the human being.

The interaction with the microbiome continues. Many saponins get broken in half once they meet pancreatic amylases, which can break sugar-to-sugar bonds, or gut flora, which can digest sugar chains for energy. But not all members of the microbiome feel the same way about saponins: probably because they are so ubiquitous in the traditional human diet, our long-term partners (the beneficial flora) aren’t harmed, and can harvest the sugars for energy. But yeasts and pathogenic bacteria that may be overgrowing in the case of dysbiosis can be damaged by saponins, whose soap-like quality melts their outer membranes. Many saponin-rich plants, like chapparal (Larrea) are excellent anti-parasitics and can help correct dysbiosis.

When you stop to think about the recent interest in the microbiome and immune system for modulating our mental health and perception of stress, our inflammatory balance, and our overall relationship with the world, you can begin to see how relevant a cocktail of plant saponins might be. The effects on immunologic tissue in the GI tract and gut flora balance is a big part of the adaptogenic, anti-inflammatory, immunomodulating effects of saponin-rich plants like Panax and Astragalus.

Some [Ref: Robb Wolf, Paleo Solutions] worry that the soap-like quality of plant saponins can “punch a hole in the lining of your gut,” contributing to leaky-gut syndrome and inflammation. In fact, these molecules can be quite toxic to fish and reptiles who lack the ability to metabolize them, and have been used as fish poisons. In these cases they do actually cause a breakdown reaction in tissues and blood cells of the animals. Fortunately, mammals seem immune to these effects (as long as the saponins aren’t injected intravenously), because our digestive enzymes and gut flora separate the hydrophilic sugars from the hydrophobic backbones, thereby destroying the soap-like effect. The hydrophobic metabolites are often absorbed into the blood, sometimes pretty quickly (less than 90 minutes), but they do no damage once they’re separated from the sugars [Ref: Lee, Jayeul, et al. "Studies on absorption, distribution and metabolism of ginseng in humans after oral administration." Journal of ethnopharmacology122.1 (2009): 143-148.]

It is these metabolites that feature prominently in the final act – but what is fascinating is that the metabolites would probably never be absorbed whole into our bloodstream if they didn’t come attached to those sugar chains. In essence, the sugars protect the hydrophobic metabolites from digestion and breakdown in the gastric phase and shield them from microbial metabolism by locking them into those little micelles. A sort of molecular enteric coating. Without it, glycyrretinic acid (the metabolite of glycyrrhizin, a licorice saponin) would never make it into our bloodstream [Ref:  崎谷陽子, et al. "Rapid estimation of glycyrrhizin and glycyrrhetinic acid in plasma by high-speed liquid chromatography." Chemical and Pharmaceutical Bulletin 27.5 (1979): 1125-1129.]

Act III – the blood and tissues

Now stripped of its sugar chains, what was once a saponin is now an aglycone – a sugarless molecule. The first tissue it encounters may be the liver (though being hydrophobic, many aglycones are absorbed into lymphatics and wind their way up to the heart instead. Soon, though, they all will visit the liver). Here, the aglycone travels across the cell membrane and begins to interact with the expression of DNA, affecting the types and quantities of proteins that are produced. Some aglycones from fenugreek saponins, for instance, seem to increase liver cells’ sensitivity to insulin, and decrease cholesterol production – thereby reinforcing the effects the saponin had in act I. Still in the liver, aglycones may interact with enzymes responsible for metabolizing sex and steroid hormones, contributing to a balancing and adaptogenic effect. Sometimes this can be quite powerful: glycyrrhetinic acid, the aglycone from licorice, slows the breakdown of secretions from the adrenal cortex such as cortisol (a stress steroid) and aldosterone (which makes us retain sodium). Taken in large quantities for long periods, it can cause fluid retention and high blood pressure.

Many saponin aglycones have noticeable anti-inflammatory effects, through a wide range of mechanisms. Some inhibit cyclooxygenases – sort of like a gentle aspirin – while others increase the presence of anti-inflammatory hormones, still others (like the aescin aglycones from horse chestnut) tone the tissue of the capillaries and venules, decreasing leakage, swelling, and pain. These actions synergize with the immunological activity exerted in act II, where the saponins talked to lymph tissue and microbiome, to reinforce the overall anti-inflammatory effect.

Because of their fat-soluble nature, a good portion (though not all) of saponin aglycones can cross the blood-brain barrier and affect the production, distribution, and balance of key neurotransmitters, particularly the ones involved in the stress response. Many adaptogens (like licorice, codonopsis, ginseng, eleuthero) rely on this activity. That horse chestnut and fenugreek lack adaptogenic activity speaks to the circulation of their aglycones: they may not be as effective at modulating the relevant hormones because they simply can’t get there.

In conclusion, we can use the example of plant saponins to illustrate the complex and multiple ways that herbal medicines interact with our physiology. They change us, in gentle but profound ways, and yet they are also themselves changed. Without this two-way interaction, none of the activities we reviewed would be possible. But what is even more interesting is that, depending on the context, all or none of these actions may be present: the same root may work differently in different folks. Codonopsis saponins might help correct dysbiosis in one individual, by preferentially feeding beneficial flora and contributing to the destruction of pathogens. This, coupled with the interaction of saponin micelles with immune cells in gut lymph, might help restore emotional and spiritual balance for that specific individual. But for another, it may be the codonopsis aglycone, interacting with the metabolism of stress hormones, that keeps their mood balanced: adrenal spikes flatten out, blood sugar normalizes, emotions stop their roller-coaster ride. The physiology can avail itself of any or all of these actions depending on what is lacking, or out of balance: and unlike single molecules like caffeine or convallotoxin, none are ever strong enough to disrupt a system already in balance. Consider saponins as great harmonizers: first in your formulas, then in your gut, and finally in your blood vessels, liver, and endocrine cells. 

Waterfowl, new moon

... with due respect to the loons ...

The great blue heron, so still, is like
a standing piece of driftwood, silver-gray cyan,
like when wood sees the pond water too long
and then, pushed up by a frost heave,
sun-bleaches and molders, gathering color.
Her neck feathers are fine grain exposed by years,
the pith and heartwood interweaving,
immobile, strong, fixed quiet to watch.

But when the neck coils down to spring
and wings open, stretching out tips
to catch sun rays in between,
you can feel the air compress
and watch her rise
as if a cord had lifted her from the granite
that lies half sunk beneath the glassy surface.

In my time I too
hope to rise that way,
fast and light and lifted,
not like the loons, who cry and flap,
and beat the water,
needing their slow, heavy ascent
to raise red eyes over the treeline.

The Kitipa boma

"The house is like a dark womb - and heavy, smoky - with a giant red eye at its core."

This boma - a Swahili word that means fence, or fortification - was about a two hour drive from Wasso hospital. We rode with ten other people in a broken-down Toyota pickup, pausing at river crossings to fill the radiator with the thick, greenish-brown water. The Maasai call their homes "engang" - the dwelling - and we arrived just before sunset, after walking about half a mile over short grasses and rocky outcrops.

Kitipa, the patriarch, was waiting, resting on a stoop just outside his home. The huts are arrayed in a circle around a thorny fence that holds the cattle at night - safe from the lion's attack, guarded by young men of the boma. Kitipa's hut is first on the right of the entrance to the cattle enclosure, a place of honor. We gave him our hand to shake, Uli bowed her head in respect and he touched it lightly. Then we moved on to his first wife's house, the next one on the right. She is the mother of my friend Nicholas, who invited us here.

"We will go into the house now," Nicholas said. It is hard to describe the home well. A small wooden door guards the entrance - about five feet tall and two feet wide. There are no windows. The outside is covered in cob made of cow dung - worn-down patches are updated with fresh dung from time to time. Thicker sticks are interwoven with a special branch - a wattle, of sorts - which serves as a scaffold for the cob. On either side of the door are branches of the sandpaper tree, Cordia monoica, placed there to protect the home from storms.

We entered into a very small antechamber. It was very dark. Immediately the senses were overwhelmed by an oppressive, acrid, hot smoke, only somewhat relieved by bending over and keeping the head low. Right in front of us, a small door led to the calves: their room occupies a third of the house. A left turn, then a right turn, led to the central dwelling space.

Here, surrounded by three gray stone slabs embedded vertically in the ground, the hearth fire was glowing. Two built-in beds, enclosed almost completely by some wattling, faced the fire and also served as sitting places. Built-in wattle shelves held cups, metal plates, calabashes of milk, tools - but you couldn't see anything, even after our eyes acclimatized to the dark. The ceiling had a crisscross network of sticks, wattle, and twigs disappearing into the darkness. Smoky cobwebs hung everywhere. The beds, made of thin sticks laid across a support structure, were covered in rawhide.

"We will not be cooking in here," Nicholas said. "It would be too hot". I was grateful. We were joined by Nicholas' brother Mangoiye, whom I had helped through a deep, feverish illness last year, and spent hours drinking hot, sweet milk, eating beans and rice, and telling stories of Maasai rituals, childhood and marriage, strange shape-shifting flesh-eating demons, warriors and cattle - all while sitting around the unblinking red eye of the hearth-fire embers.

Time came for sleep, and we reclined on the rawhide beds. It was warm, pitch black, and we could hear the low breathing of the calves. Nicholas bolted the door shut, from the inside, with a short stick polished from years of use. I fell asleep quickly - though Nicholas reminded me that at least one of the young men from the boma would be outside, guarding the cattle, keeping them safe inside their acacia thorn enclosure.

The season had been dry: no rain to green up the grass, to fatten the cattle. Almost everyone we talked to, from Wasso to the outlying bomas, complained that crops were failing, animals were hungry, rain was missing. But when I got up that night, slid the long, smooth stick out of its leather guide, and went outside to go to the bathroom, I was grateful for the cloudless sky. A huge field of stars, the galaxy silver and rippling, bright blazes of meteor trails filled my view from horizon to horizon. No human light in sight. I went back inside, overwhelmed and yet somehow so peaceful. I bolted the door, imagining what a privilege it would be to sleep out under those stars, resting with the cattle.

The next morning we woke with the roosters. A bright shaft of sunlight pierced through the home from a small hole in the eastern wall. The inside was so smoky, so dusty - you could see the beam like a shaft of pure glittering gold. We touched it, played with it like little children. Then, after some hot sweet milk, we walked outside. Mangoiye and boys were branding calves, using red-hot irons from a fire started by friction (using myrrh-tree fireboards). Immobilized by ropes, the calves made no sound as their skin, singed, let off trails of smoke into the morning air. Before walking back to the main road to get a ride back home, we talked of trees, medicine, colonial times and old games Kitipa used to play. He has many cattle, many children - a rich man.

The road home was dusty, hot and sunny. We were glad to return to hospital work, our home and our friends (and a hot-ish shower). That night we sat and talked by porch light, telling stories of the Maasai: the heat, the smoke, the dirt, the milk, the stars. We had made plans to return, speak with those who know more of the medicine trees, spend more nights in the dark of the boma home. Maasai life. If is difficult, conservative, in many ways oppressive. But in many places it is still an intact tradition - mostly, at least - and it feels special to interface with such a slice of human experience. It was an honor and a privilege.

The next morning, we experienced another privilege. The call came in - lion bite! We rushed to the minor theater. A young man, Maasai by dress, was lying on the table. Anne began chest compressions - his heart had stopped - while I took his head and positioned it to open his airway. Suddenly, he drew a huge, raspy breath. Intermittent, struggling breaths followed. I found a rapid, thready pulse on the carotid, Steve counted beats per minute on the radius. 145. We inspected his body: nothing on the legs, but his left arm had a series of deep punctures. Then we came to his head. Eye - lacerated. Pupils - fixed. Fracture above the nose. Through two gashes on either side of his head, white matter, thick and sticky, was exuding. We all realized his injuries were overwhelming: the lion had hit him in the head, his breathing sped then slowed, his heart was jumping fast and erratic. So, over the next twenty minutes, we held him as his breaths came fewer and fewer between, as his heart rate slowed, his pulse weakened. Sister Philippina poured holy water over his forehead. "Because we believe God is great." Steve lost the radial pulse. I lost the carotid. Robin stopped hearing heart sounds. He was gone.

Then the story came in from the family. He had been outside, underneath the stars, the night before, guarding the cattle in a boma's acacia enclosure. A lion had come and surprised him, he didn't have a chance to protect his head. The lion then took a cow and retreated into the night. The man was strong - he struggled a long time, refusing to give up - but in the end passed on to the fields and forest. As we felt his pulse slip away, a light rain started to fall, beating on the hospital's tin roof.