Quality Control

Video: Quality Control

Testing and Quality Control

Different countries have different regulations governing the production and manufacture of herbal supplements and it is the job of national regulatory agencies to ensure that these regulations are followed (see Purchasing for links to these regulations). The more reputable companies have rigorous quality control and testing procedures in place to ensure that what they claim to be in their products is actually there. The video follows the testing process in several companies from raw material through to finished product to see inside what some of these companies do. See Quality and Sustainability for a discussion of the broader context of quality control.

Botanical preparations include a complex matrix of hundreds or thousands of different chemical constituents acting in ways that are sometimes known, but quite often are not yet understood, to create particular effects. Contrary to conventional drugs, the so-called “active constituents” in herbal ingredients generally consist of many molecules. And for many plants, it is still a matter of debate which compounds are responsible for the beneficial properties. Good quality control depends on having the expertise and tools required to establish the identity and quality of both the raw ingredients that go into these preparations and the finished preparations. In the US and in many parts of the Western world, pharmacognosy, the scientific discipline that provides the basis of identification, quality, purity and testing of drugs developed from natural products and complex botanical materials, faded from fashion in the early 1960s, but has seen a worldwide revival with a renewed interest in integrating traditional identification methods with evolving new technologies.

Another challenge in identification is that botanicals are most often purchased in processed form, such as a powdered herb, or a dry extract. Depending on the processing, the morphological characteristics and the specific aroma and taste may be lost, and the analyst has to determine the quality based on the plant’s chemicals. And so many of the current challenges in quality control in the industry as a whole are not necessarily because people don’t want to do the right thing. They are because of the incredible complexity and variability of plants, and people may lack the knowledge and experience in identity and quality control, or the resources needed to do it.

The American Herbal Products Association (AHPA), the American Botanical Council (ABC), and the American Herbal Pharmacopeia (AHP) are some of the organizations working to preserve, enhance and perpetuate classical pharmacognosy traditions and methods. Their websites provide a wealth of resources.

ABC, AHP, and the University of Mississippi’s National Center for Natural Products Research (NCNPR)—have initiated the Botanical Adulterants Prevention Program (BAPP), a large-scale program to inform the herbal and dietary supplement industry about ingredient and product adulteration. Also see Steven Dentali’s article Successful Botanical Research Requires Botanical Expertise Clinical Pharmacology & Therapeutics 2010 87(2):149-51 for a discussion of how these skills are essential for doing the kind of botanical research necessary to understand whether and how different preparations work.

Link to discussions of regulations in the EEU.

Herb Grades

Herbs, like most commodities in trade, can be categorized into a range of defined grades and qualities. Higher grade herbs are more expensive and have more rigorous standards that must be met. Lower grade herbs are less expensive, have lower quality control standards, and are lower quality. As Josef Brinckmann writes,

“In the United States there are markets for all qualities. The highest grades of botanicals are available for quality-oriented buyers who need their herbal products to demonstrate reproducible efficacy and safety for specific intended health benefits. The lowest grades of botanicals are available for price-oriented buyers who need their herbal products to satisfy considerable consumer demand for low prices and discounts and/or shareholder demand for higher profits (“Reproducible Efficacy and Safety Depend on Reproducible Quality,” Herbalgram 2011: 41 – see Brinckmann’s article for an excellent discussion of the different standards and their impact on specific characteristics of several plants.)

As Brinckmann continues, “It isn’t so black and white. The quality needed depends on the end use, whether the botanicals will be used in food grade tea or as a botanical drug used for therapeutic purposes. Botanical products that are legally approved as botanical drugs must meet pharmacopoeial quality standards as outlined in the official pharmacopeias (books with individual monographs setting forth standards of identity, strength, quality, and purity). For approved botanical drugs, the only officially recognized pharmacopoeia in the US is the United States Pharmacopeia. Manufacturers can manufacture herbs in compliance with other quality standards such as those produced by the American Herbal Pharmacopoeia, European Pharmacopoeia, other pharmacopoeias or USP’s own Herbal Medicines Compendium. Additionally, manufacturers do not have to follow any pharmacopoeial standards at all. Instead, they can develop their own internal standard, as long as they have a scientific rationale for that standard.

Quality Control and Testing in the Herbal Supply Chain

Samples of different grades of herbs at Agrimed, Germany.

 

  • Pharmacopoeial Grade Herbs

A small number of herbal materials are approved as drug, and are required to meet existing United States Pharmacopeia (USP) monographs. That material is not necessarily different from material sold for use in dietary supplements. The difference is that a company selling therapeutic quality products must ensure that the botanicals used in these products meet the pharmacopoeial specified identity and quality standards. In contrast, products designated as food grade don’t need to meet the the same requirements.

From a sourcing perspective, the importance of finding therapeutic grade herbs means more than finding a supply of the plant. It means finding growers and collectors who know how to identify or cultivate the plant and how harvest and process it in the correct way at the right time. This is why the open market where you have no knowledge of how the material has been handled may not be a reliable source of high quality herbs. It also underscores the importance of establishing longterm relationships with suppliers.

  • Dietary Supplements 

Herbal products that are not formally approved as botanical drugs do not need to meet the requirements listed in the USP. In order to market a herbal ingredient as a new botanical drug, it must be pre-approved by FDA following a process that is both arduously time consuming and expensive. In the past 15 years, there have only been two botanical drugs that have been approved by FDA. Because of this, the overwhelming majority of herbal products that are used by consumers, patients, and practitioners for therapeutic purposes are sold as herbal dietary supplements, which are regulated as a food category, rather than as drugs. This is the primary reason why it is important to question your manufacturers about the quality control standards they follow, so you know you can have confidence in the products you are getting.

For more information, read this overview of the FDA Good Manufacturing Practices, the regulatory baseline for testing and quality control of all herbal products, written by Zoe Gardner, PhD, former Research & Development Manager and Herbalist of Traditional Medicinals.

Quality Control in the Botanical Industry

 

A tremendous amount has been written on the changing regulatory climate for herbal supplements. This topic is far beyond the scope of this website. Below we choose to highlight the identity and quality control and testing standards that are done by companies with rigorous quality control standards.

Identity and Quality Control

1. Identification

A series of tests are done to ensure plant identification.

  • Botanical Taxonomy:The identification of plants based on their morphological characteristics and genetic are the primary means by which plants are identified. The naming of plants is governed by rules codified in the International Code of Nomenclature for Algae, Fungi, and Plants. A number of companies have a direct relationship with the wildcrafter or farm from which botanical ingredients were obtained and can document the identity of the species botanically using a voucher specimen. Unfortunately, most manufacturers have no documentation that a proper botanical identification of the ingredient was made and so other tests of the harvested plant are required.
  • Macroscopic and Sensory Assessment (Organoleptics): This is one of the oldest techniques used traditionally by herbalists and herbal brokers to both properly identify and determine the relative quality of a botanical ingredient. You look at it, smell it, taste it, note the color, vibrancy, and overall quality, all of which are a reflection of the chemical profile of the plant. Does the plant part conform to what is listed in the literature? Do the leaves have the right shape? Are red clovers red, calendula flowers orange or yellow? Do the roots smell earthy or musty/moldy? Once an herb is powdered, all the identifying characteristics are gone and so other tests are required.
Identification and quality control in the supply chain

Quality control and testing at Urban Moonshine

 

  • Microscopic Assessment: The evaluation of a plant under the microscope allows visualizing additional important features, such as cell structures, hairs, pollen, vessels, or starch grains. This is often done looking at a very thin slice (cross section), e.g., of a leaf, stem, or root, or at a powdered botanical material. The shape of a trichome (hair), or the arrangement of a stoma (pore) on a leaf can help to determine the identity of a plant. In addition, excess amounts of soil, sand, or even mold can be seen using a microscope, and give important clues about the quality of the material.
  • Thin Layer Chromatography/High Performance Thin Layer Chromatography (TLC/HPTLC): This is a chemical identity test. The word chromatography defines a test or series of tests that rely on separating a sample into its constituents. It is a way of fingerprinting or chemically characterizing the herb for accurate identification or quality assessment and can be described as “a real work horse for ID.” Thin layer chromatography, through a variety of complex interactions, separates the compounds in a plant. After the separation, these compounds are visualized as bands of varying color and intensity. Relatively speaking, each plant has its own unique chromatographic fingerprint. Manufacturers often test their sample against botanical reference materials (BRMs) that have been properly identified for comparison. HPTLC, a more modern form of TLC, permits a better separation. TLC can be used to determine the relative quantity of a compound in a sample.
  • High-Performance Liquid chromatography (HPLC): HPLC is another chromatographic method that involves separation of compounds. It is one of the most widely used analytical methods by dietary supplement manufacturers. Like HPTLC, it can be used as a fingerprinting technique, but it is superior to TLC for quantitation of specific compounds. HPLC is the primary method used in industry for quantification of compounds such as the amount of caffeine in tea leaves, the amount of pungent gingerols in ginger root, or other compounds that are known to be of important for either efficacy or safety. HPLC can be combined with a number of techniques that help to visualize (detect) the compounds, e.g., the ultraviolet/visible detector (UV/Vis), evaporative light scattering detector (ELSD), or mass spectrometric detector (MS). Having an MS detector may allow the identification of compounds even when a chemical reference standard is unavailable.
HPTLC Identity testing in the botanical industry

TLC plate of linden flower (left), linden reference standard (right), and chemical reference standards of caffeic acid, hyperoside, and rutin (center). The Rf, or retention factor, is a measurement used to ensure that compounds in plants match the reference standards. Photo by Melissa Daoust / Traditional Medicinals.

 

  • Spectrometric and Spectroscopic Techniques: these include, among others, mass spectrometry (MS), and infrared (IR) and nuclear magnetic resonance (NMR) spectroscopy. IR spectroscopy is one of the most widely used assays to determine the identity and purity of excipients, but it is also used for botanical ingredients. Depending on the wavelength range used during the measurements, near infrared (NIR), mid infrared (MIR), and infrared instruments are distinguished. MS and NMR are less widely used since the instruments are more expensive, but both can provide important information about the composition of a botanical ingredient. As a stand-alone instrument (i.e., when it is not combined with a separation technique like HPLC), the spectrometric and spectroscopic techniques rely on complex statistical evaluations of the results to determine the similarity to a botanical reference material (e.g., a clinically tested botanical extract), or the batch-to-batch consistency (see below).
  • DNA Testing: DNA testing has been used to help determine the genetic relationships between families and species of plants for decades. In recent years, a variety of DNA techniques have been introduced as a potential quality control tool. DNA is highly selective in its ability to discern species when the appropriate genetic sequence of the species is known so it has the ability to distinguish between closely related species, when that is necessary. It’s most significant limitation is its inability to discern the plant part, which is a requirement of herbal supplement current good manufacturing practices (cGMPs). Another strength and limitation is that it can detect the presence of even tiny amounts of other plant species that may be mixed. This is good when trying to avoid small amounts of potentially toxic material. It is a limitation when detecting a single blade of grass in a batch and believing the batch is “contaminated” as small amounts of foreign organic matter are considered acceptable in most herbal material.
  • Marker Compound Testing: Some manufacturers include as part of the specifications or marketing the disclosure of a particular amount of a constituent, known as a “marker compound.” Varying techniques can be applied to quantify these marker compounds and not all tests quantify these equally. HPLC, discussed above, is the primary technique used for quantification of compounds. Some marker compounds are correlated with activity and others are chosen because they can be used to ensure consistency of a product or optimal harvest time of an ingredient.
  • Other Tests: There are numerous other testing techniques that can be used for assessing the quality of ingredients such as a “swelling index” for determining the amount of mucilage in herbs such as slippery elm bark and marshmallow root; or the “bitterness index” for determining the level of bitter compounds in gentian root.

2. Batch-to-Batch Consistency

Batch-to-batch consistency, important for any product, is especially important for products used for intended health benefits. Like quality, it is a huge challenge because plants by their very nature include tremendous variation. The constituents in medicinal plants responsible for healing are often part of a plant’s defense or communication systems, and they vary depending on the conditions in which the plants are grown. Plants that are stressed will typically have more of these constituents than those that are not. Thus plants sourced from different locations will likely vary in their potency and strength.

One approach to ensure batch-to-batch consistency is to mix batches with higher amounts of marker compounds with batches that contain less at a specified ratio, thus providing a consistent amount of the marker compounds. Buying from vendors who can produce relatively large lots is another way to ensure uniform consistency of the raw material. Yet, most of the companies we visited also are committed to supporting smaller growers and collectors. All of these costs and objectives must be weighed by a company when developing their sourcing strategy.

3. Procedures for Safety: Microbes, Pesticides and Heavy Metals

  • Microbes – Types of sterilization: Regulations for herbs in the US state that it is illegal to sell foods or medicines that contain pathogenic bacteria, e.g., Salmonella or E. coli. This has always been true. For herbs used as seasoning or spices, if they are not organic, it is legal to irradiate or fumigate the herbs with ethylene oxide. It is illegal to irradiate organic material.
  • If the herbs are to be used as a dietary supplement, it is illegal to irradiate the plant material. There are other options, none perfect, for ensuring the material is free of pathogens: steam treatment, dry heat, ultraviolet light, and other emerging technologies. Pathogenic material has become an issue in herbal industry, both because of food scares overall and because changing practices in how companies and consumers use the herbs. The FDA’s cGMPs state that if a dietary supplement is for direct oral ingestion and, from what you know about the supply chain, it is possible that there could be pathogenic contamination, you have to make certain that the produce (from the fields, etc.) is free of pathogens. The standard set by the FDA may be very difficult for companies to comply.
Microbial tests at an herbal products company n Poland

Microbial tests at an herbal products company in Poland

 

Regulations also affects growers, though under the food and not the dietary supplement cGMPs. The technology is still evolving. Right now, steam sterilization is the only allowable type of sterilization under organic certification, and more and more larger companies are now sterilizing all of their raw material. The technology isn’t perfect though. It is a balancing act of not changing the integrity of the plant by using too high of a temperature and using high enough temperatures to kill pathogens. Companies using steam sterilization do pre and post steam tests to compare the reduction log on microbes and the quality and appearance of the plants.

  • Pesticides: Most non-organically cultivated crops are treated with a variety of pesticides and most organic crops are subject to pesticide drift from neighboring non-organic farms. Organically certified material must meet rigorous pesticide standards that are becoming increasingly difficult in the world with more and more non-point contamination (pesticides that are getting into organically cultivated fields, e.g., from the air or from contaminated water sources).
  • Heavy Metals: The earth’s geological substrate is rich in minerals (metals). Plants have varying levels that they naturally take up from the environment and so all plants will have some level of metal. Some of these metals, in particular heavy metals like arsenic, cadmium, lead, and mercury are known to be toxic at relatively low concentrations. If plants are harvested from roadsides or industrialized areas that have higher than normal geological levels, the plants can be contaminated. Also, use of unfiltered water in the manufacture of herbal products can be a source of abnormally high levels. Many companies test for heavy metals and establish standards to minimize consumer exposure.