Alongside growing popularity among consumers has come increased governmental oversight. For instance, FDA has been ramping up enforcement of current Good Manufacturing Practices (cGMP) for dietary supplements (FDA Regulation 21 CFR 111) through inspections. As a result, many manufacturers have been compelled—or in some cases forced—to increase, or develop, testing protocols. Similarly, implementation of the Food Safety Modernization Act (FSMA) could have significant impact on the nutraceuticals landscape.
“FDA inspection and enforcement actions have skyrocketed in recent years,” said James Neal-Kababick, director, Flora Research Laboratories, Grants Pass, OR. “Many companies are working very hard to do the right thing to implement regulatory requirements for quality and safety, however, sometimes that can be challenging. The increase in FDA inspections not only ensures greater compliance but also acts as an educational process for those companies that do not have the required framework in place. It is almost like having a stop sign in a low traffic area; most people will just do a rolling stop, but if a police officer is nearby, more people will comply and come to a complete stop.”
Testing on the Rise
Analytical testing has clearly increased in the past 10-15 years, for several reasons, according to experts. Alongside the availability of more specific testing methods, noted Gabriel Giancaspro, PhD, vice president, Foods, Dietary Supplements and Herbal Medicines, U.S. Pharmacopeial Convention (USP), Rockville, MD, “the issuance of cGMPs for dietary supplements by FDA includes provisions for testing of ingredients, in process monitoring and finished products, thus providing a framework for compliance that is being monitored by FDA.” In addition, “a continuous increase in the consumption of dietary supplements, combined with numerous press reports of adulteration, has made consumers more aware and demanding of quality products.”
John Szpylka, corporate director of chemistry for Silliker, Inc., Chicago, IL, agreed that as consumers become more educated about nutraceuticals and their components, they demand more information. “With the FDA regulations in place, more formal quality systems are being established with those systems requiring testing for the release of raw materials, ingredients and finished products.”
Taken collectively, according to Bill Neumann, vice president, Quality Assurance & Regulatory Affairs, Consumer Product Testing Company, Inc. (CPTC), Fairfield, NJ, “Implementation of Good Manufacturing Practices for the dietary supplement industry, heightened FDA surveillance and an ever growing number of USP Monographs for both dietary ingredients and products have resulted in increased testing of nutraceuticals, utilizing more scientifically sound methodologies than ever before.”
Elan Sudberg, CEO, Alkemists Labs, Costa Mesa, CA, said that when his company first started testing in the nutraceuticals industry around 1997, only a handful of customers seemed truly focused on quality and efficacy. “The industry’s evolution to current day has been considerable, as it appears as though cGMP compliance is finally being taken seriously. Meanwhile, finished products have become more complex and now include novel ingredients, which require scientifically valid proprietary test methods. While the trend is undoubtedly positive and in the direction of compliance, much work is still to be done.”
Adulteration and contamination continue to present critical issues for the industry, he added. Vulnerable categories include weight loss, body building/sports nutrition and sexual enhancement products.
According to Mr. Sudberg, “Historically these products have had the unfortunate proclivity to be contaminated with active pharmaceutical ingredients (APIs), approved prescription drug ingredients, controlled substances and untested and unstudied ingredients. Through awareness and collaboration on test methods to detect these unlawful ingredients, resolution is not so far off.”
Still, adulteration of dietary supplements with APIs and/or their analogues and/or homologues remains the biggest problem currently plaguing the nutraceuticals industry, according to Alexander Schauss, PhD, FACN, CFS, senior research director, Natural and Medicinal Products Research, AIBMR Life Sciences, Inc., Puyallup, WA. “FDA has made it explicitly clear that the manufacturer who sells the finished product is responsible for that product’s contents and label claim information. If the manufacturer doesn’t leave the door open and give the (testing) lab the option of checking for adulteration, adulteration can be missed, for products that have a history of adulteration in particular.”
As for food safety, Nancy Eggink, technical service manager, 3M Food Safety Department, St. Paul, MN, said the state of testing has evolved alongside customer needs. “As food and beverage manufacturers improve their food safety and quality management systems, the requirements for testing increase. Every indication is that this is a growing requirement and that test methods and processes will move closer together in coming years.”
Pass or Fail?
FDA warning letters for failure to conduct required testing under cGMPs “illustrate the challenges that dietary supplement manufacturers face,” noted John Atwater, PhD, senior director, Verification Programs, USP.
“Having public standards and reference materials widely available to manufacturers of dietary supplements is crucial to increase and maintain quality controls in the dietary supplements industry. USP has not only been working on increasing the number of monographs available in the Dietary Supplements Compendium (DSC) as well as accompanying reference materials, but also has verification programs for dietary supplements and ingredients,” which offer companies added value in a crowded marketplace.
USP verifies product quality through a comprehensive testing and evaluation process that includes audits of manufacturing facilities, practices, records and quality control measures, “as well as laboratory testing of ingredients and products for conformance to USP standards or other applicable standards,” noted Mr. Atwater.
According to Ed Wyszumiala, general manager of NSF International’s Dietary Supplements Certification Programs, many manufacturers still struggle to comply with FDA regulations, “which is apparent given the increase in FDA warning letters issued in recent years.”
Some dietary supplements on the market may contain ingredients not listed on the label or contaminants that can be harmful, he noted. “These types of problems can lead to FDA warning letters, seizures, manufacturing injunction and damaged brands.”
NSF International’s Dietary Supplements Certification Program, which is based on NSF/ANSI Standard 173 (the only American National Standard for dietary supplements, according to Mr. Wyszumiala) helps ensure that NSF Certified dietary supplements do not contain undeclared ingredients or unacceptable levels of contaminants. The certification process requires label claim review to certify what’s on the label is actually in the bottle; toxicology review to verify product formulation; contaminant review to ensure there are no unacceptable levels of contaminants in the product; facility audits (GMP audits of the plant twice annually, based on FDA Regulation 21 CFR 111); and ongoing monitoring to certify compliance.
NSF also evaluates products that are specifically intended for use by athletes through its Certified for Sport program, Mr. Wyszumiala noted. “In addition to meeting GMP requirements and the requirements of the NSF American National Standard for dietary supplements, products also are reviewed on a lot-by-lot basis to ensure they do not contain substances banned by major sports organizations, including stimulants, narcotics, steroids, diuretics, beta-2-agonists, beta blockers, masking agents and other substances.”
Ultimately, an increase in FDA warning letters over the last five years, and reports about failures to comply with GMPs, chips away at confidence in the entire industry, Mr. Wyszumiala suggested.
“The FDA is publically reporting that 70% of the dietary supplement manufacturers it inspects are found to have some form of GMP failure,” he added. “Compare that to a GMP failure rate of less than 5% in most other FDA-regulated industries. The dietary supplement industry needs to be aware of these failures and learn from them to avoid repeating the problems found in warning letters.”
FDA has reported the same compliance issues repeatedly year after year, according to Flora Research’s Mr. Neal-Kababick. “That is a problem because some of those compliance issues are at the basic core level, like identity. One way to address this is for companies to bring in experts or consultants to help them understand the nuances of compliance.”
Keys to Compliance
Training is essential for maintaining high standards of quality assurance and compliance with GMPs, according to NSF’s Mr. Wyszumiala. “GMP regulations clearly state that employees involved in manufacturing, packaging, labeling and holding of dietary supplements must be trained in their respective roles to maintain compliance with 21 CFR 111.”
In addition, he recommended companies have their GMP systems evaluated by a fresh set of expert eyes. “NSF International developed a Dietary Supplement GMP Facility Registration Program in accordance with FDA’s GMP guidelines for dietary supplement facilities. Earning GMP registration from NSF International verifies that a dietary supplement facility has the proper methods, equipment, facilities and controls in place for producing dietary supplement products.” Nearly 400 facilities are currently registered by NSF’s GMP registration program.
Inadequate testing is one of the most common GMP infractions, according to Mr. Wyszumiala, who said testing can be broken down into three main areas: identity testing, supplier qualification testing and finished-product testing. “According to FDA reports and warning letters, many firms are still not spending enough time developing appropriate test methods to validate the identity of incoming ingredients.”
Many companies use in-house verification technology, such as Fourier transform infrared (FTIR) and near-infrared (NIR) spectrometers. NSF auditors find these technologies are commonly used, as they are relatively inexpensive and quick; however, they may not be appropriate for identifying all incoming materials, such as blends or botanicals.
“When ingredients are mixed with other compounds or are derived from plant material, if the proper validated methods are not being used, these verification techniques could potentially misidentify the botanical species or fail to detect an adulterant,” said Mr. Wyszumiala. “Also, FTIR and NIR spectrometers create a ‘fingerprint’ or data pattern of the ingredient; the more complex the ingredient, the more complex the fingerprint. The most important aspect of using this method—and where many companies continue to struggle—is establishing a reference standard of what a sample fingerprint of good, high-quality material should look like. Companies need these reference standards with which to compare incoming ingredients.”
Properly identifying incoming ingredients also protects companies from corrupt links in the supply chain. For instance, NSF auditors have observed cases in which chondroitin sulfate has been diluted with a cheaper substitute, carrageenan.
CPTC’s Mr. Neumann said that while the nutraceuticals industry in general continues to increase its level of GMP compliance, many opportunities for improvement remain. “A review of FDA-issued Form 483 observations and warning letters reveals that one of the more common deficiencies is a lack of proper quality management being exercised over the supply chain. Under GMPs, ingredient manufacturers and service providers must be qualified and continually monitored by their clients to ensure the quality of their products and services.”
Under current regulations, companies must verify the Certificate of Analysis (CofA) of incoming ingredients. “However, ingredients and their CofAs pass through many hands before making their way to a company’s facility for processing, providing plenty of opportunity for contamination or fraud along the way,” said Mr. Wyszumiala.
However, CofAs for ingredients are often a reproduction created by the distributor rather than the true CofA from the actual manufacturer. NSF auditors have seen synthetic vitamin E being sold and represented as the more expensive natural vitamin E, as well as instances in which a company sourced a high-quality version of glucosamine but after testing found that it was a much cheaper form that didn’t match the CofA. “Proper testing to verify the source eliminates this type of fraud. This is why the leading dietary supplement companies have heeded the guidance of the FDA and verify CofAs through proper testing.”
Supply chains are usually long and complex, making it hard to determine who originally manufactured the ingredient. Known cases of adulterated raw materials making their way into the U.S. have even sparked new regulations. The Food Safety Modernization Act (FSMA) in particular keys in on suppliers as a control point for preventing contaminated products from entering U.S. facilities.
NSF auditors recommended keeping the paper trail as clean and clear as possible. To ensure continued compliance to specifications and to GMPs, companies are required to perform periodic re-qualification of suppliers and testing to verify CofAs.
To help with the process of supplier qualification, the Council for Responsible Nutrition (CRN), Consumer Healthcare Products Association (CHPA) and United Natural Products Alliance (UNPA), as well as many of their member representatives, have started a collaboration known as Standardized Information on Dietary Ingredients (SIDI).
Scientifically Sound & Thorough
Testing finished products to verify the accuracy of their labels, as well as the absence of harmful levels of contaminants such as heavy metals and microorganisms, is paramount to GMP compliance, said NSF’s Mr. Wyszumiala.
While much emphasis has been placed on lead, and recently arsenic, AIBMR Life Sciences’ Mr. Schauss stressed that heavy metal testing needs to include cadmium as well. “Cadmium is a particularly potent neurotoxin that has insidious characteristics and properties in vivo from causing central nervous system damage to facilitating the development of certain cancers. It has a profoundly stronger affinity for metal protein transport compounds that deliver a range of minerals to tissues and cells, thereby competing with essential nutrients and replacing them in situ. This can lead to imbalanced ratios of essential metals such as zinc and derangements in cellular metabolism.”
Although scientifically sound testing methods are readily available, in most instances they cannot be directly applied in the testing of individual products, according to CPTC’s Mr. Neumann. “This is due to the fact that published methods are typically validated with respect to a single sample matrix (i.e., one specific product formulation). With so many active and inactive ingredients available to formulators who continue to create more and more complex products, it is not surprising that testing interferences are regularly encountered when attempting to apply these published methods to real world product samples. When testing challenges of this nature are encountered, the solution typically lies in the identification of an alternate method through a literature search and/or the conducting of method development activities.”
Testing complex finished products requires high-tech instrumentation, test methods and expertise that many companies do not have in-house, Mr. Wyszumiala added. “Some finished products have upwards of 20 to 50 different ingredients and label claims. This becomes even more complex as testing and verification involves trace amounts—micrograms and milligrams in dosage quantities. The challenge can sometimes lie in selecting the appropriate test methods and instruments.”
High-performance liquid chromatography (HPLC) is often most suitable for the analysis of various phytochemicals, he said.
Inductively coupled plasma (ICP) instruments are ideal for confirming mineral levels such as calcium, while ICP mass spectrometry (ICPMS) is needed for measuring trace heavy metal contaminants. For products containing fatty acids, such as fish oil, gas chromatography (GC) instruments are required.
Again, companies that manufacture complex proprietary blends face an even greater challenge, as there are no compendial standards to compare their finished products against. “This is why many companies seek the expertise of outside, third-party accredited laboratories to help review their formulas and develop test methods, or even perform the testing for them.”
Silliker’s Mr. Szpylka offered St. John’s wort as an example of product with a complex mixture of compounds that may present challenges with respect to analytical testing. “St. John’s wort is a botanical containing a variety of substances claimed to promote better emotional and physical health. A few examples of the substances in this product include hypericin, essential oils, flavonoids and others. The first step in creating an appropriate analytical method to identify and quantify this product is to get agreement on what components need to be quantified by the testing method(s). This is not easily done. Recently, AOAC created a working group to answer this question for St. John’s wort.”
By ensuring the quality of the ingredients and monitoring the ingredient inputs during the manufacturing process, finished-product testing can focus on those parameters that are most sensitive to change or degradation, according to Mr. Wyszumiala. “Building quality into the system can save on overall test cost and goes a long way toward achieving the ultimate GMP goal of producing and releasing only high-quality products. Sufficiently qualify suppliers by either sourcing ingredients from other third-party GMP-registered facilities and/or performing the appropriate identity testing and validation of the CofAs before ingredients go into the manufacturing process. Then, validate the blending process to ensure that the proper equipment and systems are in place to produce a consistent homogenous blend and finished product.”
In addition to testing ingredients prior to manufacturing, companies should perform testing post-manufacturing to validate relevant marker compounds in the finished products. “Thoroughly test finished products to verify formulation and label claims and to ensure that there are no unacceptable levels of harmful contaminants.”
Gitte Jensen, PhD, research director, NIS Labs, Klamath Falls, OR, said nutraceutical research has matured to incorporate novel and advanced scientific tools and testing methods. “Building a solid foundation of robust data on a product takes dedicated and focused efforts. Exploratory research will help identify areas of interest, into which further testing can drill down in much more detail.”
Overall, the industry has “grown up” significantly, she said. “To a large extent, the regulatory demands for claim substantiation has led to robust documentation of efficacy of many nutraceutical products. However, by focusing only on claims-driven research and testing, we risk losing the innovative edge of our industry. Science innovation is not a luxury; it is a survival tool in our industry.”
Understanding your product is not a trivial process, she added. No single test will provide a comprehensive understanding of a complex natural product. “Companies seeking simplistic solutions to the claims documentation for their products are on a less solid path than companies that engage in a strategic research plan, supporting a focused process of building a portfolio on each product.”
According to Robert McGregor, general manager, Global Marketing and High-End Lab Instrument Sales, Brookfield Engineering Laboratories, Inc., Middleborough, MA, another component of testing involves the need to test powders for flow behavior, which has proliferated dramatically in recent years. “Traditional instruments and methods (Flodex Cup, angle of repose measurement, tap test) do a poor job of predicting flowability. An increasing number of equipment failures on the plant floor are due to powder jams or partial blockages, which cause erratic flow. Worst-case condition is caking, which may render the powder useless for processing.”
Industry requires a test method that can predict powder flow behavior reliably, he added. “This is especially critical when transitioning new formulations to the pilot plant to evaluate processability. Shear cells are becoming the instrument of choice for characterizing flow behavior and providing processors with factual information on hopper dimensions for successful flow discharge. The test method shears powder particles to measure their frictional resistance when sliding against each other, thereby quantifying scientifically the amount of force required to cause flow.”
Other Tools and Standards
Along with a growing number of monographs and reference materials, USP’s Verification Program offers an opportunity for manufacturers to have their manufacturing operation audited according to FDA GMPs, and their products tested according to USP standards, said Mr. Atwater. “This voluntary program provides a measure of product authentication and quality that awards the ‘USP Verified’ mark, which consumers find valuable.”
USP’s Mr. Giancaspro also noted that USP hosts annual workshops where stakeholders have the opportunity to discuss the latest testing technologies and the work being done on new and improved ways to deter adulteration of foods and dietary supplements.
In September, for example, one workshop focused on tainted products containing pharmaceuticals that are marketed as dietary supplements and ways to detect and prevent adulteration in the supply chain, including improved test procedures.
“Dietary supplement ingredients are complex in nature,” said Nandakumara Sarma, PhD, director, Dietary Supplements, USP. “As a result, a single test method would not be a sufficient measure for identity, quality and purity of those ingredients. Accordingly, we emphasize the importance of compliance with all the monograph specifications, rather than a specific test procedure that may be more or less specific, to ensure that identification and quantification is achieved in a proper manner. We recommend that dietary supplement ingredients and products be tested using full USP monographs, so that if there is a test that is less specific than one could achieve for a certain ingredient or product, there are additional tests in that monograph that may be orthogonal and make up for a potential lack of specificity.”
Flora Research’s Mr. Neal-Kababick said that analytical testing has increased dramatically, and the pressure to run analyses cost effectively and in a timely manner is intense. “The longer that raw materials or finished products are held pending test results, the less profit companies make. Testing labs need to turn around tests faster with increasing demand for more types of analyses.”
CPTC’s Mr. Neumann agreed that large testing programs tend to be costly and result in a slowdown of the entire process. “This is the ‘old school’ principle of testing quality into your product. A better, ‘new school’ approach may be found in FDA’s Quality by Design initiative for the pharmaceutical industry, which is based upon qualification of vendors and service providers, gaining an in-depth understanding of one’s production processes, validation of critical process activities and a program of random monitoring/testing. Although this approach requires some up-front efforts, it leads to lower testing costs, lower inventories and faster turn-around times.”
The Path Ahead
With more FDA oversight and enforcement, USP’s Mr. Sarma said he hopes more manufacturers will be compelled to comply with the dietary supplement GMPs and thereby deliver safe, good quality products to consumers. “As testing becomes more and more specific, and more reference materials are made available, we think the industry will eventually make identification and quality testing an integral part of the dietary supplements industry.”
Helping to ensure this is the path industry follows, USP will continue to develop new monographs and reference materials for dietary ingredients and supplements, and revise existing monographs as more sophisticated, validated test procedures become available. “We believe this will bring greater consistency and improved quality of dietary supplement products for all consumers,” said Mr. Sarma.
Test method technologies will continue to make incremental improvements, according to 3M Food Safety’s Ms. Eggink, “but the implementation of FSMA could have impacts on the nutraceutical landscape, such as FDA having access to records, contract laboratories providing specialized testing and global harmonization of methods.”
Meanwhile, the challenges remain the same, according to Alkemists Labs’ Mr. Sudberg. “There will always be mistakes causing contamination, and cheaters will always cheat. The quality of this industry is in all our hands and keeping its reputation positive is critical to survival.”