In the future, the success of functional foods, botanical dietary supplements, and new botanical drugs will depend on delivering botanical components in a predictable and assured manner in order to effectively reduce the risk of disease and/or improve body structure and function.

Dietary supplement registration worldwide has become increasingly demanding due to two rationales: (1) new scientific findings in nutrition and related sciences and (2) upgraded market requirements. As the industry moves toward Western medical and commercial disciplines, scientists and marketing professionals need new tools that provide answers to nutritional challenges, sustain quality and health claims, tackle situations associated with successful management of the unpredictable, and manage science at the interface of emerging health categories.

In order to support these goals, companies need to follow a new "science-based business model" that includes the following strategies: (1) delivering predictable, efficacious, well-defined and safe bioactive components; (2) building a multi-disciplined scientific team with adequate resources funding; (3) achieving higher investment rewards via patented and innovative products; (4) working together with marketing professionals to achieve higher customer satisfaction; and (5) meeting new requirements from regulatory authorities (including serious adverse event reporting and GMPs) in the U.S. and other countries.

Scientific and quality issues are often overlooked in relation to product development, but times are changing. In order to meet the challenges of today and tomorrow, there are specific tactics and tools that can become an integral part of a corporate "Quality System" to strengthen organizational credibility and address issues of scientific sufficiency that may be lacking.

Attributes of Quality, Safety & Efficacy

A Quality System is an "umbrella" program that maintains the integrity of the organization, the product(s) and production. The system encapsulates the total lifecycle of the product, from inception of ideas through development and launch, until the product is taken out of the market ("End of Life"). A process roadmap is presented in Figure 1 (right), highlighting the key steps that need to be taken in creating a "science-based business model."

Attributes of Quality. There are three interlinked quality domains: science, product development and project management.

The scientific attributes of quality include three interrelated parts: accurate identification of content, safety and efficacy. Both safety and efficacy studies require a careful analysis and identification of the chosen botanicals (including their intermediate extracts and the end product), and should include at least the following detailed documentation: The plant name (Latin botanical name and common name if any); the actual plant part used, collection dates, geographical collection location, and where the voucher specimen (i.e., reference material) was deposited; a detailed description of extraction, drying methods and preparation; a Certificate of Analysis (CoA), an extract "fingerprint" and method of analysis; and the manufacturing protocol following the guidelines of FDA's GMPs.

Currently, some products on the shelf have raised concerns about false or misleading label content. Some independent tests have found that in several cases the claimed ingredient identification or the concentration of claimed constituents in an ingredient did not match the label claim, and/or revealed inconsistencies from batch to batch.

It is assumed that impending FDA GMPs will further address the following issues: Mislabeling of ingredients and their respective amounts; presence of drug materials and other contaminants (pathogenic bacteria, pesticides, heavy metals), including foreign materials; and improper industry production procedures, packaging and shelf life. While these are already requirements under the present food GMPs that dietary supplements fall under, new regulations will address them specifically.

Safety. Two safety issues are often overlooked. Ancient and folklore medicines are being modified from "tea style" consumption (i.e., a diluted form) to concentrates (powders and tablets) by the modern industry, with many companies banking on presumptive safety claims due to long history of use. In many cases, however, this conversion to a "new form," apart from the "traditional form," may require a New Dietary Ingredient Notification (NDI). Unfortunately, many companies in the industry appear to be unaware of this distinction and generally rely on claims based on traditional or history of use.

New mixtures of various herbs/botanicals continue to pop up frequently. At the same time, these products are being taken together with an ever-increasing number of modern prescription drugs. This development begs the question: Are these combinations safe?

To address the issues of product safety (both individually and in combination with other products) manufacturers will have to consider the following questions: In relation to toxicity, do the active compounds (if known) have negative side effects on the user, and at what dose? And in terms of compatibility, do the chemicals of one plant extract either interact with, or negatively affect the chemical constituents of another plant extract within the mix? Lastly, as far as interactions go, are there any negative interactions when taken together with common prescription medicines?

Questions related to safety can be addressed in a variety of ways, including animal testing (LD50), especially for those ingredients or NDIs with no history of safe use. Companies can also evaluate human safety via clinical trials, establishing post-marketing surveillance, and establishing a serious adverse event reporting (AER) system. (Note: A system of identifying serious adverse events was proposed in 2004, passed into law by Congress in 2006, and will become effective by the end of this year.)

In the context of interactions, it would be ideal to publish a minimum set of interactions between some of the most popular prescription medications and herbs/dietary supplements, though very little of clinical significance is actually known compared to the body of information on drug-drug interactions.

It is also important to define shelf life attributes, since quality aspects of the dietary supplement products may deteriorate with time. It is foreseeable that in the near future, companies may be required to establish formal "shelf life" studies, and provide records for accelerated stability testing and the required storage conditions, in order to meet label claims. Shelf life and stability data will correlate with "expiration date" as part of the label. Key to this effort will be the definition of the quality aspects to be monitored.

Efficacy. A critical function of quality is linking the active components in the product to the biological activity at the required dose-response level. A science-based mode of action requires examining botanicals and herbal mixtures using the following two methods: In vitro studies, which yield information at the micro or molecular level, and in vivo studies in an animal and/or human to obtain information at the macro and physiological levels.

Proof of activity, using in vivo (pharmacological) studies, addresses the following questions:

� Is there legitimate statistical proof for a positive impact?
� Does the active compound reach the biological target within the body?
� How quickly does the active compound reach its target?
� How long is the active compound kept within body fluids?
� What is the required daily dose for achieving the desired positive effect, or a maximum effect?
� Are there dosage differences between males, females and children (per unit weight)?
� How does the efficacy profile of the product change over time (shelf life attributes)?

These requirements are not necessarily applicable currently to dietary supplements in the U.S., but they could be part of a new botanical drug proposal submission. The treatment of a complex botanical ingredient is different than researching a single active compound. In this situation, showing a reasonable consistency of composition will be necessary.

Product Development

There are several quality attributes that need to be considered by product management for organizational success. These attributes must be agreed upon by all "stakeholders" during the requirements phase and include the following:

� Defining the "customer" and the "competition"
� Timely delivery within market window and budget
� Feature sets (i.e., delivery format-tablets, drinks, shakes, bars, color, taste, size)
� Price (affordable for the selected market segment)
� Usability (i.e., packaging-ease and convenience of use)
� Support sets (clear, accurate labeling, friendly instructions, multi-media relevant background material, informative advertising/infomercials, 24/7 "help desk")
� Commercial advertising and distribution channels
� Availability (everywhere, anytime)
� Aesthetics (attractive packaging, creating or following a "fashion")

Two popular methodologies that cross-reference between the market or organizational needs, and product(s) or feature-set selection, are (1) SWOT analysis (Strengths, Weaknesses, Opportunities, Threats), and (2) QFD analysis (Quality Function Deployment). Both methods help to rank and choose the new top products and/or top product features. These methodologies are particularly important when resources are limited and/or requirements contradict each other. In addition, both approaches prevent corporate "power struggles" and stabilize the priority list of products and/or product features, since they provide a formal and consistent, "semi-mathematical" analysis, thus offering the potential of cost savings, reduced risk, increased customer satisfaction, market share and a competitive edge.

SWOT analysis is a basic high level corporate strategy-building methodology that provides the basis for the development of marketing plans. The organizational (internal) strengths and weaknesses are assessed against environmental (external) opportunities and threats. The practical value of SWOT analysis is often underestimated, due to its simplicity. Once the matrix is completed, SWOT analysis offers "leads for the low hanging fruit" (where strengths plus opportunities are found). Using this approach, an organization may consider investing for the long term in the domain where weakness meets threats.

QFD requires a group decision-making process. It has been successfully used by many companies in the development of products and/or services, branding and product management. It originated in the Japanese military industry, and is currently being used in the car and communications industries worldwide. The method creates consensus across organizational boundaries, driving focus on the critical characteristics of a new or existing product(s) and/or service(s), from multiple viewpoints-i.e., the customer, market segment, company, or technology needs. The results of the technique yield a prioritization graph and/or matrix that can be re-used for future product/service development.

Project Management

The top decision maker for each product family is the product manager. He/she is responsible for the success or failure of the target product family throughout the entire product lifecycle. The product manager "sub-contracts" a project manager, who coordinates and manages the resources of the product development phase-within budget and time-by introducing a predictable "Product Development Cycle" (outlined in Figure 1), together with a suite of supportive tools.

The Requirements Phase. The deliverables of this phase are the early versions of a Market Requirements document (see Table 1, below), a Product Requirements document (see Table 2, right), and a Project Plan (see Table 3, right). These documents are intra-company communication tools and are critical in the early planning of a science-based product (refer to Figure 1, page 61). Incomplete documentation or communication generally results in poor understanding of the end user's needs, the market, the end product, the competition, and/or the organization's long- and short-term strategies. Even though this development phase is extremely important within the Product Lifecycle, many organizations bypass this phase, execute it poorly or invest too little in resources. Required investment in this phase is at least 10-15% of development resources.

A new concepts database is an important tool to use during the Requirements Phase (refer to Figure 1, page 61). A well-maintained database allows for the constant capture of innovative ideas from all possible sources and personnel. Desired project attributes that can be captured include: the target health category, potential users' profile, desired marketable features, added value, competitive products, market window, level of innovation, etc. Additional sources of information may include: formal knowledge management (e.g., commercial scientific databases and technical publications) and intelligence sourcing (i.e., sub-contracting consultants, who specialize in the domain of interest and evaluate market trends and needs, competitors' products and related success and failure market events). A database should be screened periodically by "a new concepts team," composed of scientists and marketing professionals, using SWOT and QFD analyses for project prioritization.

The Proof of Concept Phase. Top ranked selected projects pass through feasibility testing and additional market analysis. All scientific, engineering, safety and marketing issues should be resolved during this phase. Keep in mind, "killing" a project early will make the prioritization and selection process more effective later. This phase leads to pilot batch scale and encapsulates a miniature total "lifecycle" of the product, including an updated version of the Market Requirements document, Product Requirements document and Project Plan. It also entails a pilot study of safety, tolerance and efficacy, using a small-scale clinical trial.

This phase requires scholarly resources exclusively, however, usually the timetable and cost for this phase are hard to predict or maintain. Therefore, it is recommended innovation be carried out in small steps-state clearly, in advance, the boundaries of time and budget dedicated for this phase.

The Design and Implementation Phase. The design and implementation phase resolves engineering issues of scale-up, and coordination of the different parts and personnel of a complex project. The innovative part of the phase involves the design of more economic and efficient project implementation processes. The deliverables include the final versions of the following items: (1) the product design (i.e., powder, drink, bar or tablets) and related documents; (2) the consumer package; (3) training materials for all parties; (4) all "pieces" of the marketing and launch efforts (i.e., public relations documents and multi-media, including the plans to meet the media and the public); and (5) regulatory documents, and internal and government documents. At this stage, when project management is effective, predictability is expected to be relatively high. Often the "proof of concept" phase is merged together with the "design and implementation" phase. In this case, predictability is weak and implementation costs rise.

The Controlled Introduction Phase. This phase allows for both non-innovative and upgraded products ("me too" and "version 2" types of products) to be launched to the mass market, with minimal effort. In contrast, innovative products require more rigorous testing (and may require clinical trials) for safety and efficacy profiles.

The product may be minimally tweaked during this phase. However, if more than 15% changes are required, initiation of a new project ("back to the drawing board") may be necessary.

The Mass Production Phase. This phase consists of routine implementation of manufacturing, sales, monitoring market response and adoption, including routine analysis of all important product attributes-relative to an agreed set of standards-and maintaining these attributes within specifications.

In an effort to reduce costs, sources of new and cheaper ingredients, extraction processes, analytical methods, and biological tests can be established. Depending on the level of modification and/or innovation, either "a fast track," or a full-blown development lifecycle is required.

End-of-Life Phase. The "flags" that initiate the End-of-Life phase for a product ideally lack any elements of surprise, since this scenario is captured in the Requirements Document (see Table 1, previous page). The decision is based on financial/profit-margins, not strong or emotional "lobbying." Consumers are in�formed well in advance and incentives are offered to re-direct them to the "next generation" product or an alternative product.

Failing products should be "killed" as early as possible in order to prevent corporate "bleeding," due to product maintenance efforts and costs. This is a common issue faced by mature companies.

Success Stories

Market successes in the area of botanicals emphasize two points-incorporation of quality parameters and the importance of linking the chemical signal to a biological effect, leading to a therapeutic impact. The ability to demonstrate the mode of action translates to better control over appropriate dose levels, uniform efficacy and consistency in clinical studies, thereby allowing the organization to differentiate itself from the competition. To date, there are several examples of market successes.

First, in the medical food category, Limbrel (made and patented by Primus Pharmaceuticals, Scottsdale, AZ) is the first prescription product developed to meet the nutritional requirements of patients with osteoarthritis through dual inhibition of arachidonic acid metabolism. Clinical studies have shown Limbrel to be effective. It contains a proprietary blend of natural ingredients from phytochemical food sources (fruits and green tea), comprised primarily of the natural flavonoids baicalin and catechin.

Another good market example is an antioxidant from French Maritime pine bark called Pycnogenol (made and patented by Horphag Research Ltd.), which is a water-soluble flavonoid complex that represents a unique and natural combination of constant proportions of procyanidins, flavonoids and organic acids. It was recently awarded GRAS (generally recognized as safe) approval for use in functional foods and beverages. Horphag Research has invested a significant amount of money to carry out its extensive scientific research efforts over the last 30 years, assuring the safety and efficacy of Pycnogenol.

Another company headed in the right direction is Next Pharmaceuticals, Inc., Salinas, CA, which is a uniquely balanced science and marketing company that develops patented natural ingredients. Its products are licensed primarily to companies with successful consumer brands involved in the nutritional supplement and functional food markets.

A final example of how to implement a science-based model comes from Pharmanex, the dietary supplement division of NuSkin, which long ago created the "6S" process for product development. The 6S system includes: safety, sourcing, selection (of ingredients and plant parts), standardization (of chemical components) and substantiation-all are quality attributes that are supposed to lead to the sixth "S," which stands for sales.NW

References furnished upon request.

About the authors: Shuly Cooper, PhD, is president and co-founder, and Ray Cooper, PhD, is CSO and co-founder of PhytoScience Inc., Los Altos, CA. Ray Cooper is also a former employee of Pharmanex. PhytoScience is a company that creates innovative botanical solutions and products for the nutrition industry. The authors can be reached at rcooperphd@aol.com.