Chapter 107 Natural Product Quality Control
The Food and Drug Administration
The Importance of Quality Control
Finished Product Expiration Date and Stability Testing
Assessing Quality Via Comprehensive Testing
Supplier Certification and Skip Lot Testing
Laboratory Testing and Laboratory Quality
Economically Motivated Adulteration
Residual Chemical Solvents in Dietary Supplements
Dietary Supplement Pricing and Quality
Current Good Manufacturing Practice Certified Programs
Dietary supplements (DSs) are obviously beneficial to promote health, restore balance, and treat disease. People take them for long periods of time, often for years and years. A sensible strategy for limiting contaminants in DSs, making sure that they are authentic and the potency they claim to be, is to require suppliers to prove that they routinely do thorough testing to verify and assure those quality parameters. DS prescribers and consumers need to ask for legitimate proof of quality from each manufacturer.
Before launching into the details and challenges of product quality control, the author and editors want to acknowledge and commend those nutritional supplement manufacturing companies that perform most, or all, of the processes necessary for quality verification. Unfortunately, too many in the industry—retail, mail order, professional, and online—fall short in providing legitimately verified quality DSs.
Abbreviations and Definitions
DS CGMPs: Dietary Supplement Current Good Manufacturing Practices. The “current” is included because they are subject to updating and changes, and DS manufacturers are responsible for staying current with the updates in the regulations.
DS manufacturer: A company that obtains raw materials from domestic or foreign suppliers and uses those materials to manufacture, label, and sell capsules, tablets, powders, liquids, etc.
EMA: Economically Motivated Adulteration.
FDA: Food and Drug Administration.
HPLC: High performance liquid chromatography. An instrument used to analyze and check for the potency level(s) of botanical and nonbotanical raw materials and FPs.
HPTLC: High performance thin layer chromatography. An instrument used to analyze and check for the correct genus and species (identity) of botanical raw materials.
OOS: Out-of-specification (studies).
RM: Raw material, also know as a component or DS ingredient used to make the final DS.
Scientifically Valid Method: This is from the preamble section of the FDA CGMP final rule for Manufacturing, Packaging, Labeling, or Holding Operations for Dietary Supplements: “Consistent with the view that we expressed in the 2003 CGMP Proposal, we believe a scientifically valid method is one that is accurate, precise, and specific for its intended purpose. In other words, a scientifically valid test is one that consistently does what it is intended to do.”
SOPs: Standard operating procedures.
Supplier: A domestic or foreign company that sells DS raw materials, as a distributor, broker, agent, or it may be the original direct manufacturer.
Verify: To prove the truth of, as by evidence; confirm; substantiate; to ascertain the truth or correctness of, as by examination; to act as ultimate proof or evidence of; serve to confirm.
State of the Industry
There are approximately 1500 DS manufacturing companies in the United States. In addition, there are a number of marketing companies that have their DSs made by a private label contract manufacturer and sell their brand nationally or worldwide. Many of these manufacturing companies historically have performed little or no testing on their raw materials (RM) or their finished DSs. They accept a certificate of analysis (COA) from their supplier. The COA is just a piece of paper that says the material is what it is supposed to be. When a DS manufacturer blindly accepts a COA as the “sole” proof of authenticity, potency, and purity, they relinquish their verification role. Why do they do this? Because it is quick, easy, cheap and saves money, hassle, delay, and personnel. In short, they take the easy way out. This practice is likely to continue until practitioners and consumers knowledgeably demand quality or the Food and Drug Administration (FDA) clamps down and puts noncompliant manufacturers out of business or makes them comply under the threat of constant scrutiny, steep fines, or shutting down their business. The chain of events needed to produce high-quality DSs is too long and complicated to “trust” it will happen with consistent integrity without comprehensive testing of raw materials and finished products (FPs).
Pharmaceutical drugs are all too frequently sold as DSs. Unscrupulous DS manufacturers or marketing companies will sell products for weight loss, erectile dysfunction, fatigue, athletic performance, etc. These products are advertised as DSs, but the active ingredient is a pharmaceutical drug. In addition, drug and disease claims are often used in the marketing of DSs. These two practices give the DS industry a bad name, tarnishing the legitimate manufacturers and leading the FDA to mistrust companies that produce DSs.
The Food and Drug Administration
The FDA has had regulatory oversight of the DS industry for 15 years or longer. In 2007, they put into place Current Good Manufacturing Practice (CGMPs) regulations. The regulations are basically rules to follow when manufacturing DSs, much like a strict recipe that has to be followed to get the intended outcome. They are “the law,” and every manufacturer has to follow them. It has been fairly recent (since late 2007) that the FDA has been conducting inspections of DS companies to see if they are complying with the new regulations. Word on the street is that many manufacturers are not complying. Maybe they will at some point in the future, but how will you know if a particular company is, or is not, complying with DS CGMPs?
• The FDA’s mission is to promote and protect the public health by helping safe and effective products reach the market in a timely way, and monitoring products for continued safety after they are in use.
• The FDA is probably underfunded and overburdened. At present, they probably do not have the capacity to strictly oversee the DS industry and enforce wide compliance in a short period of time.
• The DS CGMP regulations were written loosely so as to be flexible. This is a serious problem because it allows each manufacturer to apply “their own” interpretation of what it will take to comply with the regulations, possibly resulting in poor quality DSs in the marketplace.
• Because the regulations were written to be flexible, the FDA gives little to no guidance on the detailed specifics of “Expected Best Practices” to DS manufacturers. The lack of FDA specific guidance parameters keeps everybody guessing as to whether or not the way “they” interpret the regulations will be acceptable to the FDA.
• The FDA will strictly enforce the DS CGMPs. As they do, it is likely to bring significant positive change to the DS industry that will ultimately benefit the consumer.
If a DS manufacturer says that they are in compliance with FDA CGMPs, it does not mean they have done enough to adequately test and verify their raw materials and FPs and to ensure that the final product is authentic, potent, and has maximum freedom from contamination. In addition, it is important to know that the FDA has mandated by law that if a product has an expiration date or best used by date on the label, the DS manufacturer has to have data to support the expiration date time period.
What data does a DS manufacturer have to show? The FDA is silent on this point. The FDA CGMPs do not give any guidance to the industry as to what is acceptable to meet this requirement. This is a perfect example of the FDA providing no guidance on an important part of the DS CGMPs and leaving it to the DS manufacturer to guess and interpret what may be adequate.
Basics of Food and Drug Administration Current Good Manufacturing Practices
Companies that supply DS ingredients (domestic or foreign) to DS manufacturers do not have to follow the FDA DS CGMPs. According to the FDA, this means that the responsibility for the quality of raw material ingredients falls on the FP DS manufacturer and not on the supplier of the materials. This is unfortunate and a major deficiency in the DS CGMPs. Why? Because companies that supply ingredients to DS manufacturers can produce and sell poor quality or tainted ingredients and are not held accountable. If the supplier of the ingredients and the manufacturer that uses the ingredients had to follow the same regulations, there would be a synergy to bring quality ingredients to the marketplace.
The following information comes from the FDA’s website (www.fda.gov), and it gives enough detail to see what DS manufacturers must do to comply with these legally required regulations. The FDA DS CGMPs are not voluntary, but must be followed because they are the law. All DS manufacturers are required to follow these rules as of June 2010.
• The current good manufacturing practices (CGMPs) final rule will require that proper controls are in place for dietary supplements so that they are processed in a consistent manner, and meet quality standards.
• The CGMPs apply to all domestic and foreign companies that manufacture, package, label, or hold dietary supplements, including those involved with the activities of testing, quality control, packaging and labeling, and distributing them in the U.S.
• The rule establishes CGMPs for industry-wide use that are necessary to require that dietary supplements are manufactured consistently as to identity, purity, strength, and composition.
• The requirements include provisions related to:
• Consumers should have access to dietary supplements that meet quality standards and that are free from contamination and are accurately labeled.
• The rule will give consumers greater confidence that the dietary supplement they use has been manufactured to ensure its identity, purity, strength, and composition.
• The rule addresses the quality of manufacturing processes for dietary supplements and the accurate listing of supplement ingredients. It does not limit consumers’ access to dietary supplements, or address the safety of their ingredients, or their effects on health when proper manufacturing techniques are used.
• Under the Dietary Supplement Health and Education Act (DSHEA), manufacturers have an essential responsibility to substantiate the safety of their products and for determining that any representations or claims made about their products are substantiated by adequate evidence to show that they are not false or misleading.
• The CGMPs will help to ensure manufacturers produce unadulterated and properly labeled dietary supplements.
• Under the CGMP rule, manufacturers are required to:
• Examples of product quality problems that the rule will help prevent are:
The regulations mandate that each DS manufacturer set, document, and meet quality specifications for raw material ingredients and FPs. Each manufacturer gets to set their own specifications based on what they feel and/or think is important and complies with the regulation to ensure the four buzz words: identity, purity, strength, and composition. Herein lies a major problem with the CGMPs. The FDA gives little if any guidance on setting specifications.
Purity is one of the buzzwords; one aspect of purity is contamination. Part 111.70 of the regulation states, “You must establish limits on those types of contamination that may adulterate or may lead to adulteration of the finished batch of the dietary supplement to ensure the quality of the dietary supplement.” No guidance is given as to the types of contamination to consider. In CGMP seminars conducted around the country in the past few years, the FDA mentioned some examples of contamination and ultimately stated that the DS manufacturer should know globally what contaminants to consider.
Here is an example to illustrate:
• DS manufacturer “A” sets a specification for testing for a wide panel of chemical solvent residues in each batch of received RMs, examines those results for acceptable limits, and approves or rejects materials based upon those limits.
• DS manufacturer “B” sets a specification for testing for chemical solvent residue only if they are listed on the suppliers’ COA, examines those results for acceptable limits, and approves or rejects materials based upon those limits.
• DS manufacturer “C” sets a specification that does not include chemical solvent residue testing.
Each DS manufacturer set a specification per the CGMPs, but each was different. Are they all acceptable to the FDA? We do not know. Which manufacturer’s products would you prefer to prescribe?
The Importance of Quality Control
The first reason quality control is very important is clinical effectiveness. In other words, will it have the intended physiologic effect on the body? Great quality does not always ensure significant clinical response, but most would agree that a low potency product or one that was not even what it claimed to be is not likely to help patients.
The second reason quality control is very important is that some sort of contamination may be present in the product. Long-term use of contaminated DSs may possibly cause harm. Depending upon whether it is botanical or nonbotanical, the contaminants present could be lead, mercury, cadmium, arsenic, an array of chemical solvents, aflatoxins (liver toxins from mold growth), herbicides and pesticides, harmful bacteria, and industrial chemicals.
Unfortunately, with RMs coming from all over the world, contamination is a risk that is unavoidable.
Food and Drug Administration Definition of Quality
The FDA DS CGMP regulation has specific definitions for quality and quality control.
• Quality means that the dietary supplement consistently meets the established specifications for identity, purity, strength, composition, and limits on contaminants, and has been manufactured, packaged, labeled, and held under conditions to prevent adulteration under section 402(a)(1), (a)(2), (a)(3), and (a)(4) of the act.
• Quality control means a planned and systematic operation or procedure for ensuring the quality of a dietary supplement.