Chapter 2
The 6S™ Quality Management of Nutraceuticals: An Operating Principle at Pharmanex 1
1
2
Andrew Chiu , Joe Chang , and Michael Chang 1
2
Pharmanex, Inc., 75 West Center Street, Provo, U T 84601 Pharmanex, Inc., 2000 Sierra Point Parkway, Brisbane, CA 94005
We describe the evidence-based 6S™ Quality Management Process that has been implemented by Pharmanex to ensure the production of the highest quality neutraceutical products for consumers. The 6S™ Process includes 6 key research elements, Selection, Sourcing, Structure analyses, Standardization, Safety and Substantiation, that govern all the steps from R & D to clinical testing and to product marketing. Key features of this process are chemical characterization of the botanical extract, identification of the biologically active components, standardization of extracts in terms of their chemical composition and bioactivity, animal toxicity studies, and controlled clinical trials to rigorously assess efficacy and safety. The development by Pharmanex of the dietary supplement Cholestin™, which maintains healthy cholesterol levels, is discussed as an example of the use of the 6S Process to produce a scientifically validated product with batch-to-batch consistency.
© 2002 American Chemical Society
11 Sales of botanical products are approaching $3.5 billion annually and 60 million American adults use herbs in their efforts to promote health. This growth in interest and the use of traditional therapies has been fueled in part by the desire of aging baby boomers to find alternatives to pharmacological drugs and by an increase in consumer awareness of the potential benefits of botanical products. Nevertheless, despite their popularity, the health claims of traditional remedies are in many cases not based on sound research into their mechanisms of action, toxicity, and clinical efficacy. Such a situation does not conform to good pharmacological practices and would not be tolerated by healthcare consumers i f it was the standard for pharmaceutical drugs. It has also given rise to the common but unsubstantiated assumptions that all herbal products are safe since they are natural, have no side effects, and are efficacious over a broad dose range. However, the lack of rigorous scientific research for the majority of botanical products must be rectified i f the reluctance of many in mainstream medicine to accept these products as medically valid is to be overcome.
Regulatory Issues Botanicals are currently regulated as dietary supplements under the Dietary Supplement Health and Education Act (DSHEA) and are defined as plant extracts, enzymes, vitamins, and hormonal products that are available to the consumer without prescription. They are limited to "structure/function" claims - that a product may affect the structure or function of the body. Since dietary supplements are not required to meet the same regulatory requirements as pharmaceutical drugs, explicit drug claims are not allowed in their labeling. This means that dietary supplements, in contrast to pharmaceutical drags, cannot be marketed for the "treatment, diagnosis, cure or prevention of a disease". One factor that may drive producers of botanicals towards generating a more scientific knowledge base for traditional herbal products may be the fact that research methodologies paralleling those used with pharmaceutical drugs will have to be used i f herbal products are to be approved by the Food and Drug Administration (FDA) as botanical drugs. The F D A has recently issued draft procedures for obtaining marketing approval for a botanical drug through an over-the-counter (OTC) monograph or a New Drug Application (NDA) (1). To be able to sell a botanical as a drug under an existing O T C monograph, a product would have to be generally recognized as safe and effective, and there would have to be existing clinical studies that confirmed the product's safety
12 and effectiveness. Botanical products not meeting these criteria would have to be approved using an N D A , which would need to include clinical studies, safety data and chemistry, manufacturing, and controls ( C M C ) information. If existing information was not sufficient to support an N D A , an Investigational New Drug (IND) application for the product would have to be submitted. Although the amount of data that would have to be supplied for the N D A would vary depending on whether the product has been marketed in the U S , outside the US or has not been marketed, considerable C M C and toxicological information might be required, along with phase I, phase II, and phase III clinical trials. Whatever the outcome of the debate over these guidelines, it appears as though regulatory approval for a disease claim for a botanical drug will require scientifically substantiated evidence similar to that required for a , pharmaceutical drug.
Components of the 6S Process If herbal extracts are to become a respected component of mainstream medicine, even though a disease claim may not be sought, we at Pharmanex believe that their composition and pharmacological properties should be rigorously defined. For example, the composition of preparations of the same herbal extract often differ from manufacturer to manufacturer and not even a single company may produce a standardized extract. This makes it difficult to compare the efficacy and safety of these extracts either in the literature or in new clinical trials. Further, the efficacy of botanicals is often based on anecdotal data and a long history of use, which is not considered satisfactory for pharmaceutical drugs. We have addressed such issues by developing the 6S™ Quality Management Process (Table I), which we believe offers a mechanism by which herbal products can be shown to be truly safe and efficacious and can be produced with a consistent pharmacological activity from different batches of raw materials. We believe that the 6S Process addresses the fundamental problems of quality control that are found throughout the natural products industry and allow Pharmanex to offer the consumer the highest quality natural healthcare products available. Chemistry Components of the 6S™ Process Natural products can be subject to variation in composition, to contamination and to deterioration, so each batch should therefore be tested for both chemical composition and biological activity. Important factors that contribute towards batch consistency include an accurate taxonomic classification of the plant species, consistent use of only the part of the plant
13
Table I. The Components of the 6S™ Quality Management Process Selection
Standardization
Review of scientific data to identify unique natural products
Consistent chemical profile
Selection of product for development base on unmet health need
Consistent pharmacological profile ensures consistent usage level
Sourcing
Safety
Raw material assessed for active or marker components.
History of safe use at recommended dosages
Quality control during harvest and storage
Toxin mid animal safety analyses
Structure
Substantiation
Identification of active constituents
Efficacy claims based on substantiated scientific claims
Active constituents assayed by state-of-the-art validated methods
Prospective clinical study performed i f necessary
14 that contains the pharmacolgically active compounds, definition of a chemically standardized extract, die absence of toxic contaminants, and the stability of the final product. Where possible, extracts should be standardized with respect to the content of the presumed bioactive components and these active constituents should be assessed by methods approved by the Methods Validation Program.
Pharmacology Features of the 6S™ Process The pharmacological activity of a natural product is very often believed to be the result of the combined actions of several of its constituents. However, in many cases the active constituents of a complex herbal extract have not been completely characterized. Chemical characterization of the product may thus not be a complete indicator of its pharmacological activity. We believe that a bioassay employing a clinically relevant activity is a better way to ensure consistency between batches of natural products with respect to the content of their bioactive constituents. This is why a key feature of the 6S approach is the investigation of the mechanism of action of the extract to identify both a molecular target for the bioassay and a surrogate molecular marker, the levels of which can be assessed as an endpoint in clinical studies. The bioavailability of active constituents is another factor that can lead to differences in efficacy between different preparations of the same herb. Indeed, low bioavailability could lead to the absence of a pharmacological effect with an extract with the same composition of active ingredients as a comparator. Again, bioassays of active components in vivo may be more appropriate than chemical analysis. Such studies are central to the determination of optimal dose and dosing regimens.
Clinical Features of the 6S™ Process Clinical research on herbal products has unfortunately often been lacking in the well-controlled clinical trials that are required by regulatory agencies evaluating conventional drugs, raising doubts about the validity of the clinical efficacy and safety of botanicals. Nevertheless, there exists the potentially dangerous assumption, especially in the absence of standardized preparations of a given herb, that botanical products are implicitly safe because they are natural products and have a long history of use. There is currently no systematic collection of data on the safety of herbal products, which has probably lead to an underreporting of adverse events and supports the general belief that herbal products have few side effects. A t Pharmanex, we believe in only making efficacy claims that are supported by well-documented scientific studies and are committed to carrying out new clinical trials to support the health claims of
15
our products. Further, we believe that adverse event data should be gathered in a rigorous, open-label safety study. The Pharmanex clinical development strategy for a product therefore includes human bioavailability studies to select a dose, an initial exploratory study using a surrogate marker of biological activity, a double-blind, placebocontrolled clinical study to assess efficacy using this surrogate marker, and a multicenter, open-label study to assess safety. The next section illustrates how the 6S™ Process has been applied to the Pharmanex product: Cholestin™, a red yeast rice extract that promotes healthy cholesterol levels.
Application of the 6S™ Process to the Development of Cholestin™ Cholesterol is a component of cell membranes and a precursor of steroid hormones that is essential for cell viability in higher animals. The body's total cholesterol level is obtained from the diet and also from that synthesized de novo in the body. Cholesterol is transported through the circulation on different types of lipoprotein particles such as low-density lipoproteins (LDL), highdensity lipoproteins (HDL) and very low density lipoproteins (vLDL) It has been long determined that a high total cholesterol level is a risk factor for cardiovascular disease. Elevated LDL-cholesterol is also a risk factor for cardiovascular disease because it promotes the formation of atherosclerotic plaque in arteries throughout the body. Oxidized-LDL particles, formed by the oxidation of circulating L D L particles by free radicals, can injure the arterial wall, stimulate the proliferation of smooth muscle cells and white cells near the inner surface of the arterial wall and induce the formation of foam cells that are the major cause of atherosclerotic lesion formation. Lowering total and L D L cholesterol levels thus reduces the risk of coronary artery disease. The rate-limiting step in cholesterol synthesis is the enzyme 3-hydroxy-3methylglutaryl-CoA reductase ( H M G - C o A reductase) and in 1979, Endo (2) discovered that a strain of Monascus yeast produced an inhibitor of cholesterol synthesis (monacolin K ) that inhibited this enzyme. This metabolite was also isolated from Aspergillus and came to be known as lovastatin (3). Cholestin is a red yeast rice extract that contains monacolins and has been shown to lower cholesterol levels, and has been developed and marketed by Pharmanex to enable people to supports the maintenance of healthy cholesterol levels.
Selection and Sourcing Red yeast rice is prepared by fermenting rice with red yeast (Monascus purpureus) and its use in China was first described in the Tang Dynasty in 800 A D . In the ancient Chinese pharmacopoeia Ben Cao Gang Mu-Dan Shi Bu Yi,
16 published in 1578, red yeast rice is recommended for improving the blood circulation (4). In China today, red yeast rice is part of the daily diet and is used to make rice wine and for food coloring and flavoring. In the West, a combination of knowledge of traditional Chinese medicine with modern biochemistry and pharmacology has resulted in the development of Cholestin as an effective dietary supplement to promote normal cholesterol levels. It is also less expensive than pharmaceutical drugs marketed for the same purpose. Application of the 6S Process ensures that this Pharmanex product has been rigorously characterized in terms of its pharmacology, long-term toxicity, and in clinical trials of efficacy and safety (Figure 1). Furthermore, Cholestin is prepared by a proprietary process that ensures each batch is standardized with respect to the content of its biologically active components.
Selection; Sourcing
Structure, Standardization Consistent manufacture of red yeastriceextract achieved
Discovery of red yeast rice in China
Product launch U.S. Trials, placebo-controlled & open-label
>
20 clinical trials in China with red yeastriceextract
Safety
Animal safety data
Cholestin™ animal efficacy demonstrated
Substantiation Figure 1. Application of the 6S process to the development of Cholestin.
Structure and Standardization Red yeast rice also contains other monacolin-related substances that inhibit H M G - C o A reductase, such as sterols (β-sitosterol, camesterol, stigmasterol, and sapogenin). Isoflavones and isoflavone glycosides, and monounsaturated fatty acids are also found. These discoveries lead Chinese scientists in the 1980's to study the benefits of red yeast rice on the cardiovascular system, and in 1993, a proprietary manufacturing process was developed for a standardized red yeast rice product which later became known as Cholestin, which reproduced the beneficial properties of the traditional Chinese extract.
17 Cholestin has been extensively characterized by Pharmanex and its composition is shown in Table II.
Table Π. Composition of Cholestin™ Red Yeast Rice Extract (6) Component Total sugars Fiber Protein Moisture Total natural pigment Ash Phosphorus Trace elements* Total HMG-CoA* reductase inhibitors (10 Monacolins) Fatty acids Saturated (palmitic and stearic) Mono- and polyunsaturated, e.g., oleic, linoleic, linolenic
Percentage by Weight 73.4 0.8 14.7 6 0.3 2.45 0.4 Trace 0.4
