Lisa Olivo, Associate Editor03.02.15
Dietary supplement use and consumer confidence are on the rise, according to the Council for Responsible Nutrition’s 2014 consumer survey, which reported that 68% of U.S. adults now use dietary supplements, and an overwhelming 83% believe in their efficacy, safety and quality. This strong vote of confidence reflects the important role that nutraceuticals play for those looking to achieve and maintain their health and wellness goals.
With such strong popularity, the nearly $35 billion industry now has a higher level of accountability to both demanding consumers and the regulatory bodies that oversee this growing marketplace.
The U.S. Food and Drug Administration (FDA) has ramped up enforcement of current Good Manufacturing Practices (cGMPs) in recent years. At SupplySide West last year Daniel Fabricant, PhD, executive director and CEO of the Natural Products Association (NPA), predicted that in the next 3-5 years the industry will see increased enforcement actions brought against companies failing to comply with the law.
Furthermore, the former director of the Division of Dietary Supplement Programs at FDA suggested the new tool set made available to regulators by the Food Safety Modernization Act (FSMA) would put the agency in better position to oversee supplement products.
Luckily for the industry, numerous validated testing methods, reference materials, and third party testing facilities are available to support companies in adhering to cGMPs, and ensuring that the supplements used by so many consumers are worthy of continued confidence.
“The nutraceutical testing industry has evolved greatly in recent years,” commented Martha Wlodek, director of product analytics, Nutrasource Diagnostics Inc., Guelph, Ontario, Canada. “There has been an increase in the use of third-party testing labs to confirm raw materials from their supply chain and rely less on the manufacturer-supplied CofAs [Certificate of Analysis]. Customers are more knowledgeable in what they want tested, and the products they are having tested are more complex than ever.”
Regulatory bodies such as Health Canada are also becoming more stringent and knowledgeable about testing of nutraceuticals, Ms. Wlodek added.
John Travis, senior research scientist, NSF International, Ann Arbor MI, said the need for dietary supplement ingredient and finished product testing is at an all-time high, with scientific and technical skills required to meet this demand rapidly developing. “Fifteen to 20 years ago, test methods were proprietary, there were no certified reference materials, and validation was an unknown term,” he said. “Now, test methods for dietary supplements are being perfected, shared and submitted to rigorous scientific scrutiny.” In fact, organizations such as AOAC International and the Office of Dietary Supplements within the National Institutes of Health are spearheading method validation efforts, he said.
While increased scrutiny can be challenging, many manufacturers and suppliers are meeting these new requirements, leading to a higher level of quality and safety throughout the industry. Key to achieving this higher standard, according to Mr. Travis, is developing and implementing scientifically valid test methods that are able to withstand rigorous scientific scrutiny. “This will greatly benefit the dietary supplement industry and foster consumer and regulatory trust by demonstrating quality through sound, scientific methods.”
Testing Standards
The first step on the path to compliance is understanding cGMPs, and determining which scientifically valid test methods must be completed in order to assure the quality and safety of ingredients and finished products.
Nandakumara Sarma, PhD, director, Dietary Supplements, of the U.S. Pharmacopeial Convention (USP), Rockville, MD, explained that “cGMPs require that the manufacturer establish product specifications for identity, purity, strength and composition, as well as limits for contaminants (21 CFR 111.70) and that the product conforms to those specifications (21 CFR 111.75).”
Manufacturers must also ensure that ingredients sourced from suppliers meet FDA’s standards based on scientifically validated test methods.
However, FDA’s requirements are generic in their expectations, Dr. Sarma said, allowing manufacturers the flexibility to use the valid testing method they prefer. “Consequently, the common language between the buyer and seller can be compromised if each is using a different test method that yields different results,” he noted.
While some manufacturers choose to develop their own private testing methods and acceptance criteria (and thereby take the responsibility of demonstrating that their methods are scientifically valid), public standards such as The United States Pharmacopeia and The National Formulary (USP-NF) offer a standardized method developed by experts in the field. USP-NF is a combination of two compendia, the United States Pharmacopeia (USP) and the National Formulary (NF). USP contains monographs for drug substances, dosage forms, compounded preparations, as well as monographs for dietary supplements and ingredients. Meanwhile, excipient monographs are in NF.
This critical testing information is compiled and assessed by volunteer experts and is open for public review, comments and revision, Dr. Sarma said. “USP’s public standards for dietary supplements are available for most of the ingredients commonly used in commerce, which can be used to help ensure the quality of ingredients in the supply chain by providing common language for both buyer and seller.”
Quality standards from USP offer essential information, he added, such as the necessary tests, procedures and acceptance criteria, as well as the highly characterized and pure chemical reference standards needed to obtain accurate results. He cautioned that, “Without a common standard, determining what passes or fails as a good quality ingredient or supplement becomes each manufacturer’s responsibility, making it difficult to determine if two ingredients or supplements that are supposed to be comparable do indeed share the same basic characteristics.” On the other hand, he said, “if two different manufacturers of a similar product follow the same USP-NF monograph, then the two products can be compared for adherence to monograph specifications.”
For finished product manufacturers, ingredient testing is an imperative aspect of supplier qualification, according to Andrea Wong, PhD, vice president, scientific and regulatory affairs with CRN. “The Standardized Information on Dietary Ingredients (SIDI) Working Group, which CRN supports, developed a supplier qualification guideline for the dietary supplement industry that includes testing recommendations,” she noted.
In addition, CRN recently compiled a database of FDA Warning Letters sent to dietary supplement companies not in compliance of certain cGMPs. The searchable database allows the industry to learn from its mistakes, and achieve better understanding of federal guidelines.
NSF’s Mr. Travis pointed to additional scientifically valid testing methods available for incoming raw materials and outgoing finished products. “AOAC International, which has spearheaded method validation efforts, is a fantastic source for these methods. Its Official Methods of Analysis contains many validated test methods for the supplement community. The peer-reviewed scientific literature is another source, but due diligence is required to ensure that the method is scientifically valid for the material being tested.”
Mr. Travis further emphasized that these tests should be conducted by “qualified personnel with the appropriate instrumentation and quality control to ensure accurate and precise results.”
Additionally, reference materials and chemical reference standards are integral to proper testing methods. However, “all reference materials and reference standards are not created equal,” Mr. Travis said. Some are certified, “which means that the producer has been accredited to follow international standards for the creation of reference materials. Others will require due diligence by the purchaser to qualify their materials and standards.”
For those looking for a specific outline of these requirements, Mr. Travis pointed to “The Selection and Use of Reference Materials (2002),” from Eurachem and ILAC-G9:2005; and “Guidelines for the Selection and Use of Reference Materials,” from ILAC (International Laboratory Accreditation Cooperation), as two exemplary resources.
“One of the greatest challenges to cGMP compliance is simply knowing what’s expected,” said Elan Sudberg, CEO of Alkemist Labs, Costa Mesa, CA. FDA’s flexible stance on what scientifically valid testing methods can be utilized can lead to difficult decisions or confusion for manufacturers. For example, Mr. Sudberg said, “Recently, an FDA audit approved one of the crudest and basic methods to identify a botanical—organoleptic—which uses taste, smell and other non-chemical tests. They stipulated, however, that only when performed in a scientifically valid manner can this ancient technique be utilized. This leaves the user at a crossroads: to be profit-hindering-ultra-compliant or consciously, willfully ignorant.”
While organoleptic testing may be an acceptable identification method for some commonplace herbs, it may be inappropriate for more exotic, complex or potent ones. Mr. Sudberg cautioned that powdered herbs should not be tested this way, and that a lab should be used in this instance. Additionally, he warned that herbs more commonly subject to adulteration should be thoroughly tested.
However, the simplicity of organoleptic analysis (and lower price tag) could lead bad actors in the industry to see this as an easy way to claim cGMP compliance, when perhaps a more rigorous identification method should be performed.
To prevent companies from falling “victim to leading with profit and not quality,” Mr. Sudberg recommended consulting organizations such as the American Herbal Products Association (AHPA) and its committees, or a trained expert.
While there are a variety of resources available for routine testing of ingredients and finished products, Gitte Jensen, PhD, research director, NIS Labs, Klamath Falls, OR, suggested the next step in supplement and ingredient testing applies to supporting marketing claims.
This “functional testing,” she said, is a bit more complicated, because its success depends on a continued working relationship with those offering the testing services.
While the industry expands and recognizes the importance of developing a strong research-based portfolio for ingredients and finished products, she said, more companies are coming around to the fact that testing is equally important “as a tool to enhance marketing efforts with regular infusions of novel data over the lifetime of a product.”
Dr. Jensen noted that the uniqueness and complexity of many natural products often lead to a need for customization. “Couple that with companies that have not had a tradition for testing their blends and finished products, and it can be difficult to determine what types of data are needed to build a robust product portfolio.”
“It is essential to work with someone who can help guide the process of creating a strategic research plan to give the best return on investment for each marketing claim. Proper planning of the timing for the various steps in testing and research will help extend the life of the product by reviving stale messages with new and exciting marketing messages,” Dr. Jensen said.
Regulatory Progress
Many dietary supplement manufacturers are bracing for how the Food Safety Modernization Act (FSMA) might impact them, and the testing methods needed for quality assurance. While FSMA was signed into law in 2011, John Atwater, PhD, senior director of verification programs for USP, said that “regulatory expectations of how companies will meet the provisions of FSMA are still in the early stages of development, and immediate impacts are yet to be seen.”
For example, he said “FSMA has a proposed rule for foreign supplier verification programs for importers of foods, which includes dietary supplements. The extent of verification activities will likely be centered on risk-based approaches rather than end-product testing—which for some manufacturers will represent a paradigm shift.” The law is intended to help ensure safety in the supply chain in a proactive manner, by trying to prevent contamination rather than reacting to it.
FSMA also serves as a tool to give more power and authority to FDA in the regulation of food products and supplements, according to Mr. Sudberg of Alkemist Labs. “Because of this, it’s likely that the FDA will be able to police its cGMPs more and in turn ensure only the safest products reach market. That’s the goal, at least.”
Tania John, MSc, associate director, Nutrition and Nutraceutical Research, for Nutrasource Diagnostics, said that FSMA is an important preventive measure that responds to numerous threats. “With globalization of the food supply, hazardous imports, on-going threats of bioterrorism and existing and emerging foodborne pathogens, FSMA will drive the industry to take a proactive and preventive position toward their food safety practices, utilizing risk- and science-based systems.”
Commenting on how the law will impact the industry, Ms. John said, “While the FSMA requirements surrounding importation, written food safety control plans, increased inspections and consumer communication may seem overwhelming, they are achievable—flexibility exists within the non-prescriptive nature of this framework. Moreover, the modernization of trading partners, compliance initiatives taken in other jurisdictions, and overall advances in food science and technology will be viewed favorably by the FDA.”
Tools & Procedures
Labs and top-of–the-line testing facilities have a variety of tools and practices at their disposal to demonstrate the purity and quality demanded by regulators and consumers.
Mr. Sudberg said proving this level of safety should be the top priority for manufacturers. “Effectiveness of a product is nothing if the product is not safe to use. This is why safety in the form of purity and potency must be established before time and money is spent proving effectiveness.”
The tools needed to verify safety are actually “old news,” according to Mr. Sudberg, with some methods dating back more than 100 years, such as light microscopy and Thin Layer Chromatography (TLC). Newer technologies, such as Ultra-Performance Liquid Chromatography (UPLC) and triple-stage quadrupole mass spectrometry (MS triple quad) were developed in the past year. These tried and true methods, plus cutting edge developments in the field equally benefit manufacturers. Mr. Sudberg believes this combination of old and new approaches provides an arsenal of scientifically validated methods available to those with the funding and diligence to set up and maintain an internal lab. “If that’s not in the cards,” he advised that “your trusted third-party lab will gladly sell you time on their machines and skilled technicians to run the tests. The biggest challenge today seems to be deciding on what tools to use.”
Dr. Sarma of USP observed that many responsible companies are utilizing multiple orthogonal methods for greater confidence in the identity and quality of their materials. These methods measure different quality attributes, which cannot be determined using a single method.
For instance, he said, “chromatography matching combined with the examination of the morphological features of a botanical ingredient are used for greater confidence regarding identity compared to testing by either parameter alone. The industry is evolving from the use of subjective or non-specific methods (such as particle size or pH) to the adoption of objective chromatographic (HPTLC and HPLC) methods for controlling the quality of the incoming materials and the final dosage forms. This is also reflected in the claims of the content of active/marker components in the dietary supplement product labels.”
Carlos Alvarez, contract auditor and technical review team member for NSF International in Queretaro Mexico, said effective process controls and specifications “allow quality to be built into a product throughout the entire production process In-process controls and specifications are a means of ensuring that a dietary supplement is manufactured, packaged and labeled in a manner that will ensure the quality of the dietary supplement is maintained and the product is produced as per the master manufacturing record.”
Mr. Alvarez also noted that a rigorous supplier qualification program is one of the most significant cGMP requirements in terms of its contribution to the quality and safety of an end product. Despite its importance, Mr. Alvarez noted that most companies continue to struggle with this cGMP requirement. With this in mind, he said “a well-functioning vendor qualification program can significantly reduce the amount of testing that has to be done on in-coming materials. It also reduces the risk of a final product becoming contaminated or adulterated.”
Trouble Spots
“Adulteration is probably the largest concern when it comes to dietary supplements,” noted USP’s Dr. Sarma, “specifically in the category of products claiming to promote sexual enhancement, weight loss or body building.”
USP has issued new proposals aimed at developing best methods for detecting and identifying adulterants. “USP is proposing General Chapter <2251> to provide tools to detect adulteration in products that claim to generate sexual enhancement,” Dr. Sarma said. The new chapter will be proposed for the Pharmacopeial Forum 41 (3) [May – June 2015] and will be available for free on USP’s website with registration. In addition, the organization is hosting a workshop, “Adulteration and Fraud in Food Ingredients and Dietary Supplements,” which will provide more insight on this topic, set to take place Dec. 3-4.
Mr. Travis with NSF International echoed concern for these three markets, saying that consumers are willing to pay a high price for products offering immediate results, which leads to an economic incentive for dishonest companies to meet their demand. “Manufacturers are required to qualify their suppliers to ensure the ingredients they are sourcing are unadulterated. Testing for adulterants such as anabolic steroids, stimulants (e.g., sibutramine, amphetamine) and PDE-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) is a necessary component of supplier qualification and often a requirement that isn’t completely fulfilled, which puts the brands sourcing these ingredients at risk,” he said.
“In addition to attracting problem ingredients, these categories attract the fly-by-night companies that have been giving the dietary supplement industry a bad name,” said Mr. Sudberg. “That certainly doesn’t mean that all these products are bad, it just means going the extra mile to ensure purity is required for those categories.”
The popularity of “high protein” claims has also led to validation issues. The test method used in the industry to determine protein content is a non-specific test, according to Mr. Travis, “which means it was designed to measure total nitrogen content and equate that to protein content by a conversion factor.” The problem with this system, he explained, is that many non-protein ingredients can also contribute to nitrogen content, and in turn lead to an inflated protein measurement.
Adding to the list of “problem children” in the industry, Mr. Sudberg pointed to “highly adulterated botanical ingredients, hidden APIs (active pharmaceutical ingredients) and designer steroids that the labs don’t even know about,” as further areas of concern.
To address the issue of adulterated botanicals, an alliance between the American Botanical Council (ABC), the American Herbal Pharmacopoeia (AHP) and the University of Mississippi’s National Center for Natural Products Research (NCNPR) created the ABC-AHP-NCNPR Botanical Adulterants Program. The consortium seeks to educate non-profit organizations, analytical laboratories, industry members, and science and healthcare professionals on the pitfalls of accidental and economically motivated adulteration. Designed as a self-regulatory body for the industry, the key goals of the organization are to determine the extent of adulteration in the U.S., and establish which analytical testing methods work best in uncovering the presence or absence of an adulterant.
Michael Abramovitz, business development manager of product analytics, Nutrasource, said vitamin testing in complex matrices needs extra attention during testing, “as companies add different amounts of overages in order to meet their label claims over the product’s shelf-life.” To prevent such issues, Mr. Abramovitz advised companies “use a lab with experience in vitamin testing in order to ensure that the most accurate results are obtained.”
Dr. Jensen of NIS Labs described challenges facing both chemical and biological testing. “Adding test products to living cells in laboratory tests is different than consuming a test product, and more is not always better. In bioassays it is crucial to include initial testing of the optimal dose range, before actually performing tests on living cells.”
Proper handling of the test product while in the lab is also critical. “If a product is not handled such that the active components are extracted and introduced to the test, then the resulting report can be meaningless.” With the support of a responsible and experienced team, or third-party lab, understanding in these transactions can be streamlined, and lead to a cleaner, effective and safe end product.
With such strong popularity, the nearly $35 billion industry now has a higher level of accountability to both demanding consumers and the regulatory bodies that oversee this growing marketplace.
The U.S. Food and Drug Administration (FDA) has ramped up enforcement of current Good Manufacturing Practices (cGMPs) in recent years. At SupplySide West last year Daniel Fabricant, PhD, executive director and CEO of the Natural Products Association (NPA), predicted that in the next 3-5 years the industry will see increased enforcement actions brought against companies failing to comply with the law.
Furthermore, the former director of the Division of Dietary Supplement Programs at FDA suggested the new tool set made available to regulators by the Food Safety Modernization Act (FSMA) would put the agency in better position to oversee supplement products.
Luckily for the industry, numerous validated testing methods, reference materials, and third party testing facilities are available to support companies in adhering to cGMPs, and ensuring that the supplements used by so many consumers are worthy of continued confidence.
“The nutraceutical testing industry has evolved greatly in recent years,” commented Martha Wlodek, director of product analytics, Nutrasource Diagnostics Inc., Guelph, Ontario, Canada. “There has been an increase in the use of third-party testing labs to confirm raw materials from their supply chain and rely less on the manufacturer-supplied CofAs [Certificate of Analysis]. Customers are more knowledgeable in what they want tested, and the products they are having tested are more complex than ever.”
Regulatory bodies such as Health Canada are also becoming more stringent and knowledgeable about testing of nutraceuticals, Ms. Wlodek added.
John Travis, senior research scientist, NSF International, Ann Arbor MI, said the need for dietary supplement ingredient and finished product testing is at an all-time high, with scientific and technical skills required to meet this demand rapidly developing. “Fifteen to 20 years ago, test methods were proprietary, there were no certified reference materials, and validation was an unknown term,” he said. “Now, test methods for dietary supplements are being perfected, shared and submitted to rigorous scientific scrutiny.” In fact, organizations such as AOAC International and the Office of Dietary Supplements within the National Institutes of Health are spearheading method validation efforts, he said.
While increased scrutiny can be challenging, many manufacturers and suppliers are meeting these new requirements, leading to a higher level of quality and safety throughout the industry. Key to achieving this higher standard, according to Mr. Travis, is developing and implementing scientifically valid test methods that are able to withstand rigorous scientific scrutiny. “This will greatly benefit the dietary supplement industry and foster consumer and regulatory trust by demonstrating quality through sound, scientific methods.”
Testing Standards
The first step on the path to compliance is understanding cGMPs, and determining which scientifically valid test methods must be completed in order to assure the quality and safety of ingredients and finished products.
Nandakumara Sarma, PhD, director, Dietary Supplements, of the U.S. Pharmacopeial Convention (USP), Rockville, MD, explained that “cGMPs require that the manufacturer establish product specifications for identity, purity, strength and composition, as well as limits for contaminants (21 CFR 111.70) and that the product conforms to those specifications (21 CFR 111.75).”
Manufacturers must also ensure that ingredients sourced from suppliers meet FDA’s standards based on scientifically validated test methods.
However, FDA’s requirements are generic in their expectations, Dr. Sarma said, allowing manufacturers the flexibility to use the valid testing method they prefer. “Consequently, the common language between the buyer and seller can be compromised if each is using a different test method that yields different results,” he noted.
While some manufacturers choose to develop their own private testing methods and acceptance criteria (and thereby take the responsibility of demonstrating that their methods are scientifically valid), public standards such as The United States Pharmacopeia and The National Formulary (USP-NF) offer a standardized method developed by experts in the field. USP-NF is a combination of two compendia, the United States Pharmacopeia (USP) and the National Formulary (NF). USP contains monographs for drug substances, dosage forms, compounded preparations, as well as monographs for dietary supplements and ingredients. Meanwhile, excipient monographs are in NF.
This critical testing information is compiled and assessed by volunteer experts and is open for public review, comments and revision, Dr. Sarma said. “USP’s public standards for dietary supplements are available for most of the ingredients commonly used in commerce, which can be used to help ensure the quality of ingredients in the supply chain by providing common language for both buyer and seller.”
Quality standards from USP offer essential information, he added, such as the necessary tests, procedures and acceptance criteria, as well as the highly characterized and pure chemical reference standards needed to obtain accurate results. He cautioned that, “Without a common standard, determining what passes or fails as a good quality ingredient or supplement becomes each manufacturer’s responsibility, making it difficult to determine if two ingredients or supplements that are supposed to be comparable do indeed share the same basic characteristics.” On the other hand, he said, “if two different manufacturers of a similar product follow the same USP-NF monograph, then the two products can be compared for adherence to monograph specifications.”
For finished product manufacturers, ingredient testing is an imperative aspect of supplier qualification, according to Andrea Wong, PhD, vice president, scientific and regulatory affairs with CRN. “The Standardized Information on Dietary Ingredients (SIDI) Working Group, which CRN supports, developed a supplier qualification guideline for the dietary supplement industry that includes testing recommendations,” she noted.
In addition, CRN recently compiled a database of FDA Warning Letters sent to dietary supplement companies not in compliance of certain cGMPs. The searchable database allows the industry to learn from its mistakes, and achieve better understanding of federal guidelines.
NSF’s Mr. Travis pointed to additional scientifically valid testing methods available for incoming raw materials and outgoing finished products. “AOAC International, which has spearheaded method validation efforts, is a fantastic source for these methods. Its Official Methods of Analysis contains many validated test methods for the supplement community. The peer-reviewed scientific literature is another source, but due diligence is required to ensure that the method is scientifically valid for the material being tested.”
Mr. Travis further emphasized that these tests should be conducted by “qualified personnel with the appropriate instrumentation and quality control to ensure accurate and precise results.”
Additionally, reference materials and chemical reference standards are integral to proper testing methods. However, “all reference materials and reference standards are not created equal,” Mr. Travis said. Some are certified, “which means that the producer has been accredited to follow international standards for the creation of reference materials. Others will require due diligence by the purchaser to qualify their materials and standards.”
For those looking for a specific outline of these requirements, Mr. Travis pointed to “The Selection and Use of Reference Materials (2002),” from Eurachem and ILAC-G9:2005; and “Guidelines for the Selection and Use of Reference Materials,” from ILAC (International Laboratory Accreditation Cooperation), as two exemplary resources.
“One of the greatest challenges to cGMP compliance is simply knowing what’s expected,” said Elan Sudberg, CEO of Alkemist Labs, Costa Mesa, CA. FDA’s flexible stance on what scientifically valid testing methods can be utilized can lead to difficult decisions or confusion for manufacturers. For example, Mr. Sudberg said, “Recently, an FDA audit approved one of the crudest and basic methods to identify a botanical—organoleptic—which uses taste, smell and other non-chemical tests. They stipulated, however, that only when performed in a scientifically valid manner can this ancient technique be utilized. This leaves the user at a crossroads: to be profit-hindering-ultra-compliant or consciously, willfully ignorant.”
While organoleptic testing may be an acceptable identification method for some commonplace herbs, it may be inappropriate for more exotic, complex or potent ones. Mr. Sudberg cautioned that powdered herbs should not be tested this way, and that a lab should be used in this instance. Additionally, he warned that herbs more commonly subject to adulteration should be thoroughly tested.
However, the simplicity of organoleptic analysis (and lower price tag) could lead bad actors in the industry to see this as an easy way to claim cGMP compliance, when perhaps a more rigorous identification method should be performed.
To prevent companies from falling “victim to leading with profit and not quality,” Mr. Sudberg recommended consulting organizations such as the American Herbal Products Association (AHPA) and its committees, or a trained expert.
While there are a variety of resources available for routine testing of ingredients and finished products, Gitte Jensen, PhD, research director, NIS Labs, Klamath Falls, OR, suggested the next step in supplement and ingredient testing applies to supporting marketing claims.
This “functional testing,” she said, is a bit more complicated, because its success depends on a continued working relationship with those offering the testing services.
While the industry expands and recognizes the importance of developing a strong research-based portfolio for ingredients and finished products, she said, more companies are coming around to the fact that testing is equally important “as a tool to enhance marketing efforts with regular infusions of novel data over the lifetime of a product.”
Dr. Jensen noted that the uniqueness and complexity of many natural products often lead to a need for customization. “Couple that with companies that have not had a tradition for testing their blends and finished products, and it can be difficult to determine what types of data are needed to build a robust product portfolio.”
“It is essential to work with someone who can help guide the process of creating a strategic research plan to give the best return on investment for each marketing claim. Proper planning of the timing for the various steps in testing and research will help extend the life of the product by reviving stale messages with new and exciting marketing messages,” Dr. Jensen said.
Regulatory Progress
Many dietary supplement manufacturers are bracing for how the Food Safety Modernization Act (FSMA) might impact them, and the testing methods needed for quality assurance. While FSMA was signed into law in 2011, John Atwater, PhD, senior director of verification programs for USP, said that “regulatory expectations of how companies will meet the provisions of FSMA are still in the early stages of development, and immediate impacts are yet to be seen.”
For example, he said “FSMA has a proposed rule for foreign supplier verification programs for importers of foods, which includes dietary supplements. The extent of verification activities will likely be centered on risk-based approaches rather than end-product testing—which for some manufacturers will represent a paradigm shift.” The law is intended to help ensure safety in the supply chain in a proactive manner, by trying to prevent contamination rather than reacting to it.
FSMA also serves as a tool to give more power and authority to FDA in the regulation of food products and supplements, according to Mr. Sudberg of Alkemist Labs. “Because of this, it’s likely that the FDA will be able to police its cGMPs more and in turn ensure only the safest products reach market. That’s the goal, at least.”
Tania John, MSc, associate director, Nutrition and Nutraceutical Research, for Nutrasource Diagnostics, said that FSMA is an important preventive measure that responds to numerous threats. “With globalization of the food supply, hazardous imports, on-going threats of bioterrorism and existing and emerging foodborne pathogens, FSMA will drive the industry to take a proactive and preventive position toward their food safety practices, utilizing risk- and science-based systems.”
Commenting on how the law will impact the industry, Ms. John said, “While the FSMA requirements surrounding importation, written food safety control plans, increased inspections and consumer communication may seem overwhelming, they are achievable—flexibility exists within the non-prescriptive nature of this framework. Moreover, the modernization of trading partners, compliance initiatives taken in other jurisdictions, and overall advances in food science and technology will be viewed favorably by the FDA.”
Tools & Procedures
Labs and top-of–the-line testing facilities have a variety of tools and practices at their disposal to demonstrate the purity and quality demanded by regulators and consumers.
Mr. Sudberg said proving this level of safety should be the top priority for manufacturers. “Effectiveness of a product is nothing if the product is not safe to use. This is why safety in the form of purity and potency must be established before time and money is spent proving effectiveness.”
The tools needed to verify safety are actually “old news,” according to Mr. Sudberg, with some methods dating back more than 100 years, such as light microscopy and Thin Layer Chromatography (TLC). Newer technologies, such as Ultra-Performance Liquid Chromatography (UPLC) and triple-stage quadrupole mass spectrometry (MS triple quad) were developed in the past year. These tried and true methods, plus cutting edge developments in the field equally benefit manufacturers. Mr. Sudberg believes this combination of old and new approaches provides an arsenal of scientifically validated methods available to those with the funding and diligence to set up and maintain an internal lab. “If that’s not in the cards,” he advised that “your trusted third-party lab will gladly sell you time on their machines and skilled technicians to run the tests. The biggest challenge today seems to be deciding on what tools to use.”
Dr. Sarma of USP observed that many responsible companies are utilizing multiple orthogonal methods for greater confidence in the identity and quality of their materials. These methods measure different quality attributes, which cannot be determined using a single method.
For instance, he said, “chromatography matching combined with the examination of the morphological features of a botanical ingredient are used for greater confidence regarding identity compared to testing by either parameter alone. The industry is evolving from the use of subjective or non-specific methods (such as particle size or pH) to the adoption of objective chromatographic (HPTLC and HPLC) methods for controlling the quality of the incoming materials and the final dosage forms. This is also reflected in the claims of the content of active/marker components in the dietary supplement product labels.”
Carlos Alvarez, contract auditor and technical review team member for NSF International in Queretaro Mexico, said effective process controls and specifications “allow quality to be built into a product throughout the entire production process In-process controls and specifications are a means of ensuring that a dietary supplement is manufactured, packaged and labeled in a manner that will ensure the quality of the dietary supplement is maintained and the product is produced as per the master manufacturing record.”
Mr. Alvarez also noted that a rigorous supplier qualification program is one of the most significant cGMP requirements in terms of its contribution to the quality and safety of an end product. Despite its importance, Mr. Alvarez noted that most companies continue to struggle with this cGMP requirement. With this in mind, he said “a well-functioning vendor qualification program can significantly reduce the amount of testing that has to be done on in-coming materials. It also reduces the risk of a final product becoming contaminated or adulterated.”
Trouble Spots
“Adulteration is probably the largest concern when it comes to dietary supplements,” noted USP’s Dr. Sarma, “specifically in the category of products claiming to promote sexual enhancement, weight loss or body building.”
USP has issued new proposals aimed at developing best methods for detecting and identifying adulterants. “USP is proposing General Chapter <2251> to provide tools to detect adulteration in products that claim to generate sexual enhancement,” Dr. Sarma said. The new chapter will be proposed for the Pharmacopeial Forum 41 (3) [May – June 2015] and will be available for free on USP’s website with registration. In addition, the organization is hosting a workshop, “Adulteration and Fraud in Food Ingredients and Dietary Supplements,” which will provide more insight on this topic, set to take place Dec. 3-4.
Mr. Travis with NSF International echoed concern for these three markets, saying that consumers are willing to pay a high price for products offering immediate results, which leads to an economic incentive for dishonest companies to meet their demand. “Manufacturers are required to qualify their suppliers to ensure the ingredients they are sourcing are unadulterated. Testing for adulterants such as anabolic steroids, stimulants (e.g., sibutramine, amphetamine) and PDE-5 inhibitors (e.g., sildenafil, tadalafil, vardenafil) is a necessary component of supplier qualification and often a requirement that isn’t completely fulfilled, which puts the brands sourcing these ingredients at risk,” he said.
“In addition to attracting problem ingredients, these categories attract the fly-by-night companies that have been giving the dietary supplement industry a bad name,” said Mr. Sudberg. “That certainly doesn’t mean that all these products are bad, it just means going the extra mile to ensure purity is required for those categories.”
The popularity of “high protein” claims has also led to validation issues. The test method used in the industry to determine protein content is a non-specific test, according to Mr. Travis, “which means it was designed to measure total nitrogen content and equate that to protein content by a conversion factor.” The problem with this system, he explained, is that many non-protein ingredients can also contribute to nitrogen content, and in turn lead to an inflated protein measurement.
Adding to the list of “problem children” in the industry, Mr. Sudberg pointed to “highly adulterated botanical ingredients, hidden APIs (active pharmaceutical ingredients) and designer steroids that the labs don’t even know about,” as further areas of concern.
To address the issue of adulterated botanicals, an alliance between the American Botanical Council (ABC), the American Herbal Pharmacopoeia (AHP) and the University of Mississippi’s National Center for Natural Products Research (NCNPR) created the ABC-AHP-NCNPR Botanical Adulterants Program. The consortium seeks to educate non-profit organizations, analytical laboratories, industry members, and science and healthcare professionals on the pitfalls of accidental and economically motivated adulteration. Designed as a self-regulatory body for the industry, the key goals of the organization are to determine the extent of adulteration in the U.S., and establish which analytical testing methods work best in uncovering the presence or absence of an adulterant.
Michael Abramovitz, business development manager of product analytics, Nutrasource, said vitamin testing in complex matrices needs extra attention during testing, “as companies add different amounts of overages in order to meet their label claims over the product’s shelf-life.” To prevent such issues, Mr. Abramovitz advised companies “use a lab with experience in vitamin testing in order to ensure that the most accurate results are obtained.”
Dr. Jensen of NIS Labs described challenges facing both chemical and biological testing. “Adding test products to living cells in laboratory tests is different than consuming a test product, and more is not always better. In bioassays it is crucial to include initial testing of the optimal dose range, before actually performing tests on living cells.”
Proper handling of the test product while in the lab is also critical. “If a product is not handled such that the active components are extracted and introduced to the test, then the resulting report can be meaningless.” With the support of a responsible and experienced team, or third-party lab, understanding in these transactions can be streamlined, and lead to a cleaner, effective and safe end product.
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DNA barcoding does not have the capacity to reach the degree of certainty represented by allegations. The American Herbal Products Association (AHPA) stated that the New York State Attorney General used an inadequate and unproven analytical method to test herbal supplement products at the core of the state’s allegations that several retailers are selling adulterated and/or mislabeled herbal dietary supplements. The results of this analysis, therefore, cannot be considered valid. According to AHPA Chief Science Officer Maged Sharaf, PhD, the New York State Attorney General and the laboratory that conducted the analysis relied on an analytical technology that does not have the capacity to reach the degree of certainty represented by the state in its accusations. “Using DNA barcoding as the only method for identifying ingredients in popular herbal dietary supplements and ignoring all other well-established and validated methods of herbal analysis is a suspect analytical process at best, and likely to provide results that are inaccurate,” Dr. Sharaf said. “DNA testing is an emerging technology that has the potential to be useful in the future when it has been rigorously tested and validated—the usual course with new analytical methodologies,” said AHPA President Michael McGuffin. “Even after maturity, DNA testing is foreseen by the scientific community to play a complementary role to other well-established and validated techniques such as various forms of chromatography, microscopy and organolepsis,” Dr. Sharaf added. Some of the known limitations of DNA barcoding is its inability, in most cases, to identify extracts and highly processed herbal products due to the loss or denaturation of DNA material during processing. DNA barcoding may also provide misleading results by disproportionally amplifying minor components in a product, which could erroneously imply its higher content in the tested product. “It appears that many, if not all, of the products the New York State Attorney General tested were herbal extracts and this processing would likely disrupt or destroy the DNA,” Dr. Sharaf said. “If an herbal product manufacturer used this analysis, without any additional confirmation, to prove that an herbal extract is accurately identified, the U.S. Food and Drug Administration (FDA) would almost certainly dismiss this as inadequate to verify identity.” Another factor that undermines the legitimacy of this analysis is the lack of data released by the Attorney General. |
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Synutra Pure identifies testing methods to ensure safety in the chondroitin sulfate supply chain. A novel and potentially dangerous adulterant was discovered in the chondroitin sulfate supply chain, which led experts at Synutra Pure, Rockville, MD, to advocate for an effective set of testing methods to root out the contaminant. Initially dubbed, “Zero One” (Z1), the adulterant sodium hexametaphosphate was determined to be the main chemical constituent in detergents such as Calgone. While small amounts of the chemical are not considered harmful, if the level of contamination makes up 10% of the supplement serving size it could contribute to calcium depletion in consumers. Since chondroitin is a popular joint health supplement, this could be especially dangerous for users. Synutra Pure led the charge for better testing for this contaminant, speaking out about which testing methods could best detect it. The most commonly used chondroitin assay method, cetylpyridinium chloride (CPC) titration, however, was found to be easily fooled by several known adulterants, including Z1. Consequently, Synutra Pure highly recommends using cellulose acetate membrane electrophoresis (CAME) first to test for purity, followed by CPC for assay. Synutra Pure’s journey fighting chondroitin sulfate adulteration began three years ago, when it was exploring methods to weed out alginates, the most common chondroitin adulterant. Weiguo Zhang, CEO, Synutra Pure was on a mission. “I became so focused on this that I even built a wet lab in my basement to perform CAME and separate known adulterants in chondroitin, including ‘alginate sulfate diester’ (ASD), properly known in chemistry as propylene glycol alginate sulfate sodium,” he said. ASD cannot be detected using only the CPC testing method. Without using CAME to screen out this adulterant, a CPC test may be falsely elevated by ASD, which can produce a CPC reading as chondroitin at 140% by itself. The company expanded its efforts with collaborations with scientists and researchers at the University of Maryland, USP and University of Modena, Italy. While concluding its research, the company was made aware of a disturbing discovery. “As we were about to share our findings on alginates with the industry, our manufacturing plant was called on by unnamed vendors off the street to peddle a substance they claimed could effectively enhance the appearance of chondroitin potency as measured by CPC. And indeed, when our team ran a CPC on the substance, it produced a reading of 235% as ‘chondroitin,’” said Mr. Zhang. This evidence was submitted to FDA, and Synutra Pure became a vocal proponent for proper testing for this previously unknown adulterant. “Fortunately, we have CAME, an easy and effective screening method, which can detect known adulterants including ASD and this new substance,” Mr. Zhang noted. The findings from the investigations around Z1 were published in the November/December 2014 issue of the Journal of AOAC International. |
