Clarification On The Difference Between Cistanche Ratio And Standard Extract.

5 Plant to extract ratios: Definitions and misconceptions

It is important to clarify the concept of Plant to Extract ratios because misunderstandings regarding what they signify are common. Plant to Extract ratios reflect the amount of material extracted from plant biomass relative to the starting amount of biomass. They may be used to partly define extracts with or without the presence of added excipients. The calculations of Plant to Extract ratios should be made on the dried basis irrespective of whether the starting raw material used in the extraction is in fresh or dried form.‡

Similar to the EMA guidelines, the Kooperation Phytopharmaka (2016) defines the plant drug to extract ratio (DER) as the ratio of the amount of starting plant used to produce a certain amount of native extract that is exclusive of any carriers or other excipients. For example, a dry extract with an average native extract ratio of 10:1 means that approximately 10 g of dried raw material were required to produce 1 g of native/genuine extract.

In practice, native extract production yield will usually vary due to the inherent variation of extractive matter from different batches of starting materials; this results in a Plant to Extract ratio range in place of a single ratio. For example, using the same extraction conditions, one 100-kg lot of starting plant material may yield 14 kg of native extract while a different 100-kg lot may yield only 11 kg of extract. The Plant to Extract ratio in this case would be the range of 7 through 9 to 1, expressed as 7–9:1 (100 divided by 14 equals approximately 7, and 100 divided by 11 equals approximately 9). Only 7 kg of starting material would be needed to produce 1 kg of native extract in the first instance while 9 kg of another lot of the same plant would be required to produce an equivalent amount of extract.

Extract yields are fundamental to the calculation of Plant to Extract ratios. Perhaps the most common misconception regarding Plant to Extract ratios is that a higher ratio represents a stronger, and therefore better extract. Extract yields depend on the extraction process and the amount of extractable material in the starting plant biomass; Plant to Extract ratios describe the extract yield from a given raw material using a given manufacturing process. Consider a hypothetical case where all the starting material is converted to dry extract. In this case, the extract yield would be 100 percent and the Plant to Extract ratio would be 1:1,§ indicating that each unit of extract represents an equivalent amount of starting material. However, for most dry botanical materials extracted in aqueous or hydroethanolic solvents, the amount of extractable matter (soluble constituents) from the biomass is usually between 10 and 25 percent, which calculates to starting plant mass to dry extract ratios of 10:1 and 4:1, respectively (100 divided by 10 is 10, and 100 divided by 25 is 4).

The Australian Therapeutic Goods Administration (TGA) Guidance on Equivalence of Herbal Extracts in Complementary Medicines (Australian Government. Department of Health, 2011) states: “Whilst a high native extraction ratio is generally reflective of a targeted extraction procedure (i.e., specific components or component classes are selected for), there are instances where a high extraction ratio may simply reflect a partial extraction procedure.” For example, if a plant biomass with a potential 25% extractable crude material could have an extract ratio of 4:1 with a given manufacturing process but only yields 10% extractible materials of interest with a different process and leaves behind the other 15%, the extract ratio calculation changes from 4:1 to 10:1.

Low or high Plant to Extract ratios can be explained, in part, by the soluble extractive matter starting value. For example, woody roots may naturally contain relatively small amounts of extractable material and result in relatively high extract ratios even when extracted to exhaustion. According to the Hong Kong Chinese Materia Medica Standards, eleuthero root should contain not less than 3.0% water-soluble extractives and 3.0% ethanol-soluble extractives (using the cold extraction method in both cases) (Chinese Medicine Division and Department of Health, 2005a), thus a theoretical native extract ratio of about 33:1. In contrast, Asian ginseng root should contain not less than 27.0% water-soluble extractives and 22.0% ethanol-soluble extractives (using the cold extraction method in both cases) (Chinese Medicine Division and Department of Health, 2005b), thus a theoretical native extract ratio of about 4:1.

Another example of the challenge of using Plant to Extract ratios to compare botanical extract products on the market is illustrated by the case of Asian ginseng. The USP Asian Ginseng Root and Rhizome monograph sets out quality specifications for the dried roots and rhizomes of Panax ginseng, including minimum concentrations for ginsenosides Rg1, Re, Rf, Rb1, Rc, Rb2, and Rd. However, for dried raw material of a given age, the relative contents of ginsenosides Re, Rf, Rb1, Rc, Rb2, and Rd are significantly higher in the fibrous root portion > rhizome > branch root > main root, while the content of Rg1 is highest in the rhizome > branch root > fibrous root > main root (Pan et al., 2021). The rhizomes and main roots are often separated from smaller branch roots and fibrous roots in the material of commerce. Thus, a higher Plant to Extract Ratio would be needed using main root and rhizome material to achieve the same levels of the marker ginsenosides compared to extracts of the branch and fibrous roots.

As previously mentioned, high Plant to Extract ratios may also reflect manufacturing processes intentionally designed to capture only a narrow range of native constituents, either through use of a selective solvent for initial extraction or through further processing of crude extracts to concentrate specific constituents. For example, the USP Native Gymnema Extract monograph states that the ratio of starting plant material to extract is about 8:1. In contrast, USP Purified Gymnema Extract, prepared by further processing of USP Native Gymnema Extract, has a ratio of starting material to extract of about 25:1 because about two thirds of the native extract is discarded during preparation. Thus, in the case of the USP Native Gymnema Extract, it is evident that 100 g of starting material yields about 12.5 g of native extract, from which it is possible to create about 4 g of the purified extract (USP Purified Gymnema Extract).

Regarding extracts made from materials that yield high Plant to Extract ratios, the TGA makes this very important point: “Consideration should be given to ensuring that these extracts are not marketed in a manner that implies that they are “better” because they are derived from a larger quantity of raw herbal material. Such marketing would represent a misuse on the part of a supplier and a misunderstanding by customers” (Australian Government. Department of Health, 2011).

Click Here To Get Cistanche  With 30% Echinacoside

6 Plant-to-extract ratio and phytoequivalence

Botanical extracts are multi-component mixtures that can be produced to an acceptable consistency but are not usually completely uniform due to raw material variations and differences in manufacturing conditions. A full chemical comparison and/or biological testing may be needed to establish phytoequivalence between extracts so that the extracts can be assumed to be equivalent for all intents and purposes. Plant to Extract ratios that allow the calculation of starting material equivalents may serve as a criterion, along with other factors, to establish equivalence between different extracts (Health Canada, 2015). This applies only if sufficient manufacturing information about the finished extracts is available. This should include, at a minimum, the native extract concentration, extraction solvents used, and the general extraction procedure including steps applied to concentrate or remove constituents or classes of constituent (Australian Government. Department of Health, 2011). Ultimately, fingerprint characterization of constituents and quantification of marker or active compounds, as described in different sections of the USP botanical extract monographs, may be needed to fully establish phytoequivalence between extracts.

The Australian TGA Guidance on Equivalence of Herbal Extracts in Complementary Medicines (Australian Government. Department of Health, 2011) identifies the following as some of the factors that impact the phytoequivalence of extracts: starting material quality, solvent choices, and manufacturing processes including time and temperature. In relation to the solvent system, in cases where the type and amount of solvent used to manufacture a particular extract is the same, TGA states that a limited degree of variation in minor solvent concentration is now considered acceptable. In this way, extracts with small differences in extraction solvent systems may be considered phytoequivalent while excluding other solvent systems that could result in significant variation between extracts (Australian Government. Department of Health, 2011).

The addition of carriers and other excipients to extracts is another important aspect that should be addressed in the description of botanical extracts. According to the Australian TGA (Australian Government. Department of Health, 2011), “there are also situations where an extract with a high native extract ratio is diluted with a carrier or diluent, for a variety of purposes. The addition of diluents and carriers should always be taken into account when assessing whether two extracts are equivalent.”

The importance of differentiating between finished extracts containing excipients and 100% native extracts can be illustrated by considering finished extract ratios. For example, if an average of 4 kg of starting material is required to produce 1 kg of native extract, the average Plant to Extract ratio is 4:1. Adding 1 kg of carrier to each kg of native extract doubles the amount of total finished extract. Whereas the starting material to native extract ratio is still 4:1, the addition of carrier results in each kg of finished extract now containing 0.5 kg of native extract and 0.5 kg of excipient(s). The ratio of Plant to (finished) Extract (that is 50% native) is now 2:1. Without appropriate disclosure of the percentage of native extract or the percentage of excipients, a Plant to Extract ratio of 2:1 for this finished extract could imply a higher extraction yield than the original native extract ratio of 4:1. Therefore, accurate calculations of extract starting material equivalents require access to information regarding the percent of native extract and excipients in the finished extract.

7 Plant-to-extract ratio labeling

Plant to Extract ratio product labeling is required in some countries and not others, depending in part on the regulatory framework applicable for the finished product, i.e., whether the article is regulated as a food, a supplement, an over-the-counter (OTC) drug product, or a prescription drug product. This section covers ingredient labeling recommendations that are transferable to finished product labeling. Examples of Plant to Extract labeling guidelines from the Uniited States, Canada, and Australia are provided below.

7.1 Ingredients

In the United States, if a dietary supplement manufacturer claims that a dietary supplement ingredient meets USP standards, the product is misbranded (and thus unlawful) if it fails to actually meet those standards. The USP Guideline for Assigning Titles to USP Dietary Supplement Monographs (United States Pharmacopeia (USP), 2019) provides extensive details on the different types of botanical extracts for which monographs have been published, and how USP creates monograph titles that are part of the labeling requirements.

The USP General Chapter <565> Botanical Extracts (United States Pharmacopeia (USP)) in the USP–NF and in the USP Dietary Supplements Compendium states the following requirement for extract labeling: “Label it to indicate the name of the plant part used; the names of solvents, other than the hydroalcoholic solvents, used in preparation; the content, in percentage, of active principles or marker compounds identified in the individual monograph; and the name and concentration of any added antimicrobial or other preservative. Where active principles are unknown, the ratio of starting material to final product is stated. For semisolid extracts and powdered extracts, the identity and quantity of any added excipient is also indicated. In such cases, the percentage of native extract may also be stated.”

USP monographs for botanical extracts include Composition tests for percentage limits of identified active principles or marker compounds; manufacturers may also disclose both the extract ratio and excipient content. The EMA, in the 2010 Guideline on Declaration of Herbal Substances and Herbal Preparations in Herbal Medicinal Products/Traditional Herbal Medicinal Products (European Medicines Agency (EMA), 2010), recommends including the percent quantity of genuine extract, the DER (drug to genuine/native extract ratio) of the extract, and the percent amount of excipients in the declaration of ingredient descriptions, as can be seen in the following example:

Dry extract from Valerian root.

Quantity of the genuine extract: 80% genuine extract.

DER genuine: 3–6:1.

Other excipients: 20%

Extraction solvent: Ethanol 70% V/V.

7.2 Dosage forms

For dry (often referred to as “powdered”) extracts, Title 21 of the United States Code of Federal Regulations (21 CFR) section 101.36(b) (U.S. Department of Health and Human Services, 2012) (3) (ii) (C) states that “[f]or a dietary ingredient that is an extract from which the solvent has been removed, the weight of the ingredient shall be the weight of the dried extract.”

In the case of liquid extracts, 21 CFR 101.36(b) [U.S. Department of Health and Human Services, 2012] (3) (ii) (B) states that for any dietary ingredient that is a liquid extract from which the solvent has not been removed, the quantity listed must be the volume or weight of the total extract. Information on the condition of the starting material must be stated when it is fresh and may be indicated when dried material was used to make the extract. Information may be included on the concentration of the dietary ingredient and the solvent used. The United States Food and Drug Administration (FDA) provides the following as an example: “fresh dandelion root extract, x (y:z) in 70% ethanol, where x is the number of mL or mg of the entire extract, y is the weight of the starting material, and z is the volume (mL) of solvent.”

AHPA developed a retail labeling guidance for non-liquid botanical extracts titled Guidance for the Retail Labeling of Dietary Supplements Containing Soft or Powdered Botanical Extracts (American Herbal Products Association, 2000). This guidance includes carriers and other excipients as part of the quantity of a finished extract, which represents how bulk extracts are bought and sold–by total weight. AHPA also provides guidance on the voluntary disclosure of the percent of the native extract when it is listed on the label.

AHPA provides the following convention when manufacturers state extract ratios (American Herbal Products Association, 2000): “the first number shall represent the amount of dried botanical starting material, the second number shall represent the amount of finished total extract (emphasis added). For example, a 4:1 extract is one in which each kilogram (or other unit) of finished total extract represents the extractives from 4 kg (or other unit) of dried botanical starting material.” Following this convention, the amount of excipient is included in the calculation of starting material to finished extract.

AHPA offers two options for stating Plant to Extract ratios when lot-to-lot variation is encountered. These options are: 1) stating the range for either the native extract percent or for the extract ratio, or 2) using an average of the range when the range does not vary by more than 20% between the highest and lowest values (American Herbal Products Association, 2000). Two options also are provided for listing average extract values on a label, namely “average x% native” or “average x:1”. In practice, single values given for extract ratios generally represent a shorthand for the actual range. Additional information on extract ratios can be found in AHPA’s 2003 White Paper: Standardization of Botanical Products (American Herbal Products Association, 2003) and the 2000 Guidance for the Retail Labeling of Dietary Supplements Containing Soft or Powdered Botanical Extracts (American Herbal Products Association, 2000).

EMA (European Medicines Agency (EMA), 2010) guidelines provide detailed examples of how to declare Plant to Extract ratios that include disclosure of the percent excipients added to botanical extracts. The disclosure of excipients is directly translated to retail labeling of finished products. Following the earlier example of the Valerian root dry extract, Table 2 describes the correct labeling of a finished product (capsule) containing this ingredient.

The Natural and Non-prescription Health Products Directorate (NNHPD) in Canada specifies the listing of extract ratios on labels with the quantity of dried material used to make it, with the following as an example: Black Cohosh (6:1 extract) .... 40 mg, (Actaea racemosa) (root) equivalent to 240 mg of Black Cohosh (Health Canada, 2016). Since the amount of native extract or excipients is not specified, the extract ratio in this case takes into account the total amount of extract, including any added excipients, in order to represent the herb raw material equivalent.

The Medicine Labels Guidance on TG O 91 and TG O 92, version 2.3 from the Australian TGA (Australian Government. Department of Health, 2021), states: “If the active ingredient in your medicine is a herbal preparation, its quantity must be expressed as the: weight of that preparation, and equivalent weight of the herbal material from which it was prepared.” Where “standardisation” is claimed (“the process in which the content of a specific chemical constituent(s) has been determined in a herbal material or herbal preparation”), “then the quantity of the active ingredient must be expressed as: the weight of that preparation, the minimum weight of the herbal material from which it was prepared, and the quantity of standardised constituent(s) in the herbal preparation.”

The USP Asian Ginseng Root and Rhizome Dry Extract example demonstrates the effect of the addition of excipients on both the native and final extract ratios. This article is prepared from the dried roots and rhizomes of Panax ginseng C.A. Mey. by extraction with water or hydroalcoholic mixtures. It contains not less than 3.0% of ginsenosides Rg1, Re, Rb1, Rc, Rb2, and Rd combined, calculated on the anhydrous basis, and may contain other added substances. If ten parts of starting material yields two parts of native extract, a 5:1 ratio of Plant to native Extract is obtained (10 divided by 2). If 0.5 part of excipient is added to the two parts of native extract, then the ratio of Plant to finished Extract becomes 4:1 (10 divided by 2.5 is 4). Best practices for labeling of the finished total extract ingredient according to USP General Chapter <565> Botanical Extracts [United States Pharmacopeia (USP)] and its corresponding communication in the finished product are as described in Table 3.

The Natural and Non-prescription Health Products Directorate (NNHPD) in Canada specifies the listing of extract ratios on labels with the quantity of dried material used to make it, with the following as an example: Black Cohosh (6:1 extract) .... 40 mg, (Actaea racemosa) (root) equivalent to 240 mg of Black Cohosh (Health Canada, 2016). Since the amount of native extract or excipients is not specified, the extract ratio in this case takes into account the total amount of extract, including any added excipients, in order to represent the herb raw material equivalent.

The Medicine Labels Guidance on TG O 91 and TG O 92, version 2.3 from the Australian TGA (Australian Government. Department of Health, 2021), states: “If the active ingredient in your medicine is a herbal preparation, its quantity must be expressed as the: weight of that preparation, and equivalent weight of the herbal material from which it was prepared.” Where “standardisation” is claimed (“the process in which the content of a specific chemical constituent(s) has been determined in a herbal material or herbal preparation”), “then the quantity of the active ingredient must be expressed as: the weight of that preparation, the minimum weight of the herbal material from which it was prepared, and the quantity of standardised constituent(s) in the herbal preparation.”

The USP Asian Ginseng Root and Rhizome Dry Extract example demonstrates the effect of the addition of excipients on both the native and final extract ratios. This article is prepared from the dried roots and rhizomes of Panax ginseng C.A. Mey. by extraction with water or hydroalcoholic mixtures. It contains not less than 3.0% of ginsenosides Rg1, Re, Rb1, Rc, Rb2, and Rd combined, calculated on the anhydrous basis, and may contain other added substances. If ten parts of starting material yields two parts of native extract, a 5:1 ratio of Plant to native Extract is obtained (10 divided by 2). If 0.5 part of excipient is added to the two parts of native extract, then the ratio of Plant to finished Extract becomes 4:1 (10 divided by 2.5 is 4). Best practices for labeling of the finished total extract ingredient according to USP General Chapter <565> Botanical Extracts [United States Pharmacopeia (USP)] and its corresponding communication in the finished product are as described in Table 3.

References

American Herbal Products Association (2000). AHPA guidance policy. Retail labeling of dietary supplements containing soft or powdered botanical extracts. Available at: https://www.ahpa.org/Portals/0/PDFs/Policies/Guidance-Policies/AHPA_Retail_Labeling_DietarySupplements_ContainingSoftPowderedBotanicalExtracts.pdf.

American Herbal Products Association (2021). FAQs about herbal products. Available at: http://www.ahpa.org/Consumers/HerbalFAQ.aspx.

American Herbal Products Association (2003). Standardization of botanical products: White paper. Available at: http://www.ahpa.org/News/LatestNews/TabId/96/ArtMID/1179/ArticleID/225/White-Paper-Standardization.aspx.

Australian Government. Department of Health (2011). Therapeutic goods administration. Guidance on equivalence of herbal extracts in complementary medicines. Available at: https://www.tga.gov.au/publication/guidance-equivalence-herbal-extracts-complementary-medicines.

Australian Government. Department of Health (2021). Therapeutic goods administration. Medicine labels. Guidance on TGO 91 and TGO 92. Version 2.3 Available at: https://www.tga.gov.au/medicine-labels-guidance-tgo-91-and-tgo-92.Awang, D. (2004). Standardization of herbal medicinal productsLE Craker et al Acta Hort. In Proc. XXVI IHC – Future for Medicinal and Aromatic Plants, 629, 111–114.

Chinese Medicine Division, Department of Health (2005). “Acanthopanacis Senticosi Radix et Rhizoma seu Caulis,” in Hong Kong Chinese Materia Medica standards, vol 6 Hong Kong: Government of the Hong Kong special administrative region, the people’s Republic of China.

Chinese Medicine Division, Department of Health (2005). “Radix ginseng,” in Hong Kong Chinese Materia Medica standards, vol 1 Hong Kong: Government of the Hong Kong special administrative region, the people’s Republic of China.

Dentali, S. (2013). Botanical basics: Botanical extracts: Not single chemical ingredients. Montvale, NJ: Nutraceuticals World. Available at: https://www.nutraceuticalsworld.com/issues/2013-04/view_columns/botanical-basics-botanical-extracts-not-single-chemical-ingredients/.

Dieuaide, F., Tung, C., and Bien, C. (1935). A study of the standarization of digitalis. I. A method for clinical standardization. J. Clin. Invest. 14 (6), 725–731. doi:10.1172/JCI100720

Ask for more:

Email:wallence.suen@wecistanche.com 

Whatsapp/Tel:+86 15292862950