Dietary Supplement Product Testing: Real-World Challenges

Two years have passed since implementation of the Dietary Supplement Current Good Manufacturing Practices (cGMP) rule. From FDA facility inspections to analytical testing, the regulation was designed to bring sweeping changes to the dietary supplement industry.

Within the cGMPs, manufacturers are charged with validating the identity, purity, strength, and composition of dietary supplements by utilizing suitable methods that are “appropriate for the tests performed and the materials being tested.”

Admittedly, a little over 24 months does not allow sufficient time to responsibly determine how well dietary supplement manufacturers are responding to the heightened testing bar. It does, however, afford us an opportunity to discuss a few key learning points (KLPs) and address other industry issues-most notably the Food Safety Modernization Act-that have come to the fore.
 

Artificial Inflation

Dietary supplements have long been a target of economic adulteration, prompted by high costs associated with purified extracts and quality materials. Industry observers also readily acknowledge that analytical methods are sometimes manipulated by organizations seeking to claim they use the highest-quality materials. Here are a few scenarios:

Chondroitin Sulfate:The United States Pharmacopeia (USP) designates FTIR, CPC titration assay, and a lesser-known method-electrophoresis purity testing-to identify this material, which is a common target of adulteration. Many companies employ FTIR to perform identity testing. Though a powerful tool, FTIR is not infallible. Some materials claiming to be pure chondroitin sulfate can show an FTIR very similar to the USP reference material. After CPC titration, however, the material could very well reveal itself to consist of just 15% pure material.

Occasionally, another chondroitin sulfate “wannabe” may be analyzed as pure by both FTIR and CPC titration assay. During electrophoresis, however, the appearance of an additional band reveals that the material is not as pure as originally thought.

Key Learning Point: Several methods may be required to ensure the quality, purity, and composition of dietary ingredients. Go the distance.Polyphenols:The popularity of antioxidants in products, ranging from dietary supplements to sports drinks, has made polyphenols a sizzling commodity. As a result, the number of available methods for measuring polyphenols can fill a modest grocery store display case. As such, it is not difficult to come across materials with polyphenol content claims greater than 95%. When analyzed with an industry-consensus method, however, some materials fail to measure up, oft-times prompting an investigation of the method that was utilized by the manufacturer or vendor.

From experience, we know it is not uncommon for manufacturers to end up with two polyphenol values for the same material. The method used by the vendor, which may have been demonstrated to render less-than-reliable results in reputable proficiency trials, may show the material content at >95%. The second method, validated by a recognized authority, may find the polyphenol content for the same material at >70%. Consequently, the manufacturer is left with a perplexing dilemma: Should it go with the findings from the vendor’s method, or the consensus method?

KLP: When in doubt, protect the reputation of your company and choose the consensus method. It’s a smart business decision that can save you trouble down the road.Turmeric:This is another common herbal often sold in a standardized extract, to contain 95% curcuminoid content. A laboratory review may find the level to be below the label claim when compared to the raw-material vendor’s certificate of analysis. This time, the investigation may show that very similar test methods were utilized and that the only significant difference was the choice of reference calibration standards. Through a side-by-side analysis of the standards, the raw-material vendor’s standards may be found to have a lower purity than claimed. In this particular instance, the vendor was using a secondary standard material due to the high costs of the primary standards.

Using secondary standards is an acceptable practice, but secondary standards should be checked periodically against primary source standards to ensure the validity of results. Primary standards should also be periodically repurchased due to the improving quality of these standards as well as degradation concerns. This is especially true of herbal active compounds. (Case in point: Do you still have pounds of bis-demethoxycurcumin sitting in storage that were purchased during the Clinton administration?) Standards suppliers are getting better, substantially improving the accuracy of test methods. Standards that claim to be 99% pure may not be. If a conflict arises between two sources, picking the one that gives a passing result is not scientifically valid.

KLP: Learn and understand everything possible about your analytical test methods so you’ll know exactly what you are getting. (Note: In addition to turmeric, within the last few years significant differences have been recorded in reported versus actual purity for several reference standards from different suppliers for boswellic acids, epigallocatechin gallate, andrographalide, and other herbs.)
 

Unique Properties

Dietary supplements have unique properties that must be understood by manufacturers to help ensure product quality and safety. Products like garlic and cinnamon possess antimicrobial properties that can interfere with testing. If manufacturers have not properly validated their microbial testing methods, erroneous data-or even false negative results-for pathogens and indicator organisms can occur.

Therefore, it is important to perform preparatory microbiological testing. USP has published preparatory testing procedures for dietary supplement products. A common mistake manufacturers make is failing to validate how well a method performs on their matrix. The antimicrobial properties of a product could mask the presence of contamination. Once blended or consumed, the product’s antimicrobial properties could fall below required thresholds, allowing a low level of contamination to ruin the product. In dry products, organisms can persist-some of which can cause illness at low levels.

KLP: Microbial contamination can cause illness at low levels. Performing preparatory testing is vital to demonstrate the ability of analytical testing methods to recover present microorganisms.
 

Nick of Time

Many dietary ingredients degrade over time. Heat, moisture, light, microbes, and other ingredients can greatly speed product degradation, magnifying the importance for manufacturers to conduct stability testing.

For example, vitamin D and calcium, through a synergistic effect, improve absorption and are commonly formulated together in tablet form. Scores of manufacturers use coated vitamin D raw material to augment product stability. However, mixing uncoated vitamin D and calcium can result in rapid degradation. Conversely, product degradation can occur slowly over time.

Stability testing allows manufacturers to more accurately project product stability, identify processing shortcomings that can go unnoticed, and make necessary formulation changes. If manufacturers are unaware of how their ingredients and formulations degrade, they could release products to the marketplace that do not meet minimum concentrations. FDA recently issued several warning letters to manufacturers for failing to meet these criteria.
 

Absolute Necessity

Contaminant testing is an absolute necessity in today’s dietary supplement world. Almost weekly, reports are published of dietary supplements being contaminated with active pharmaceuticals, microorganisms, heavy metals, melamine, pesticides, residual solvents, and other contaminants. CGMPs specifically state that specification limits should be established for contaminants that are likely to be present in dietary ingredients and their components.

While it would be impossible to test for every possible contaminant, establishing robust specifications that address high-risk contaminants, ranging from pesticides and residual solvents in herbal products to steroids in muscle-building formulations, should be a top priority. Next, manufacturers should identify likely contaminants for their ingredients/products and establish testing specifications and protocols to verify compliance.
 

Only the Qualified Need Apply

As indicated above, analytical testing for dietary supplement testing can be complex and cumbersome. This has prompted growing numbers of manufacturers and vendors to outsource this all-important function to contract laboratories. Making a solid and informed decision when choosing an outside testing provider requires a significant investment in time and shoe leather.

In today’s social media world where hard-earned reputations can be altered in a matter of minutes, who you choose as your testing provider says much about your commitment to safety and quality. Failure to select a laboratory that delivers consistent and reliable services can undermine your reputation and business. During your initial research, it is essential to ascertain if the laboratories have:

• Written core standard operating procedures for the performance of properly documented methods, as well as schedules for the regular calibration of all laboratory equipment

• Certification of routine participation in proficiency programs that are designed to verify testing results

• Records verifying employee training and competency

On-site good laboratory practices (GLP) audits provide invaluable opportunities for manufacturers to interact with the management teams of prospective facilities and to view laboratory operations firsthand. This is an opportune time to ask such questions as:

• Do you use lab environmental testing to verify that samples and tests are not contaminated in the lab?

• Is media sterility productivity and selectivity monitored for every lot of media produced for use in microbiological testing? How are chemical reagents traced and verified before use?

• What type of daily checklist do you use to verify that methods are completed accurately?

• How often do your employees receive updated training and verification of competency?

• Do your technicians work in more than one area of the lab? If so, can I see their training verification for each area?

• How do you ensure confidentiality of results? How is security maintained in your laboratory information management system (LIMS)?

• How do you notify clients if results are “suspect” or out of specification?

• Do you employ standard methods with sufficient validation data?

• Do you undergo audits by both internal and external auditors? 

By and large, ISO-accredited laboratories have demonstrated a commitment to going above and beyond industry norms. A certificate of analysis from an ISO-accredited laboratory signifies that your product has been tested under the highest standards, ensuring the integrity and consistency of your results. When choosing a contract laboratory, this internationally recognized benchmark cannot be undervalued.
 

Preaching Prevention

The passage of the Food Safety Modernization Act (FSMA) in January marked the most sweeping change in U.S. food safety in 60 years. The dietary supplements industry will be significantly impacted under FSMA, but the aftershock will not be detrimental. Many of the new provisions are intended to bolster the safety procedures and programs used in the manufacture of mainstream processed foods and dietary supplements.

FSMA represents a major shift in FDA’s food-safety approach, placing an increased emphasis on prevention of foodborne illness as opposed to reacting, after the fact, to outbreaks. It gives greater enforcement powers to FDA (increased inspections, company document access, mandatory recalls, and increased fees) and requires companies to develop a comprehensive food-safety plan based on hazard analysis and preventive controls. To foster compliance with the FSMA guidelines, dietary supplement companies should:

• Evaluate current hazard analysis plans

• Review traceability capabilities throughout the supply chain

• Ensure all company documents and records are inspection-ready

• Review supplier specifications and selection processes, including supplier audit program sufficiency

• Evaluate imported raw materials and/or finished goods and your importers’ qualifications and documentation

• Monitor FDA’s ongoing hearings, guidance, and rulemaking activities, and participate when appropriate

Thus far, industry response to FSMA has been positive and has drawn the support of a number of leading groups, including the Council for Responsible Nutrition and the American Herbal Products Association (AHPA). “AHPA remains committed to ensuring the highest quality and consumer confidence in dietary supplements and manufacturers, and we intend to participate in the FSMA implementation process throughout its development,” said AHPA president Michael McGuffin.

FDA is sponsoring ongoing education meetings on FSMA, with topics ranging from preventative controls to HACCP (Hazard Analysis and Critical Control Points) implementation, to help dietary supplement companies understand the nuances of the new rules and comply with mandatory provisions.

Four for the Road: KLPs in Review

• Several methods may be required to ensure the quality, purity, and composition of dietary ingredients. Go the distance.

• When in doubt, protect the reputation of your company and choose the consensus method. It’s a smart business decision that can save you trouble down the road.

• Learn and understand everything possible about your analytical test methods so you’ll know exactly what you are getting.

• Microbial contamination can cause illness at low levels. Performing preparatory testing is vital to demonstrate the ability of analytical testing methods to recover present microorganisms.