Throughout 2015, the reliability of the dietary supplement raw material supply chain was called into question, notably by state attorneys general, as well as by other sources outside and within the industry. That theme looks likely to continue in 2016, with ever more focus on improving the quality and purity of ingredients, particularly botanicals, and ways for manufacturers to better qualify their suppliers and raw materials.
Failure to qualify the supplier of dietary supplements components—through confirmation of the results of their tests or examinations—while relying on the supplier’s certificate of analysis (CoA) remains in the top 10 FDA inspection observations cited on Form 483s for fiscal year 2015. This is apparently one of the most misunderstood and challenging cGMP (current good manufacturing practice) requirements to meet. Since 2008, about 200 firms have found this item on their 483, and combined with related observations for supplier qualification, the total number of citations in this enforcement area is more than 300.
Most dietary supplement manufacturers want to qualify their supplier’s CoA so they can release components without having to test all specifications each time they receive raw material. The benefits of doing this are two-fold: reducing the overall cost of testing, and improving the turnaround time from receiving a component to releasing it for use in manufacturing. The relevant cGMP sections for supplier qualification are included in 21 CFR 111.75(a)(2). The most important and frequently cited in FDA inspections is: “You did not qualify a supplier of a component by establishing the reliability of the supplier's certificate of analysis through confirmation of the results of their tests or examinations." In other words, if a company relies upon the test results on the supplier’s CoA for quality control (QC) purposes when it inspects and releases the component for use, it must first establish the results are reliable, usually by conducting independent tests and examinations. However, the cGMPs remain largely silent on exactly how establishing reliability is to be achieved, except for specifying you must confirm the test results. In other words, historical relationships, supplier questionnaires and supplier audits are insufficient to fully meet this requirement. You must do actual testing.
Before a company can qualify a CoA, it needs to know how and what it is qualifying. Also, the cGMP rules about what results a company can rely upon depend on the type of ingredient. For dietary ingredients, a company can never rely upon the supplier’s CoA to establish the identity of the component—a brand must verify the identity (using an appropriate, scientifically valid method) each time it receives the component [21 CFR 111.75(a)(1)(i)]. For other components (that are not dietary ingredients), a company may rely upon the identity and other data for component purity, strength and composition, and limits on contaminants that may appear on the CoA, but only if it has been qualified [21 CFR 111.75(a)(2)]. Other relevant cGMP rules are included in 21 CFR 111.70(b), and state you must establish component specifications for identity, purity, strength, composition and limits on contamination. It is important to establish those specifications for the raw material prior to embarking on a supplier CoA qualification program. Specifications provide guidance for what items on the CoA a brand needs to qualify—and the acceptance range or limits—to maintain the final quality of a finished dietary supplement.
A good raw material qualification program must establish and consider:
• Which characteristics and specifications tested on the supplier’s CoA are important to product quality?
• Will acceptance limits be broader or narrower than the supplier’s limits?
• Are the tests listed on the supplier’s CoA performed using appropriate, scientifically valid methods?
• Which laboratory will be used to qualify the CoA results, and has the brand ensured it has the appropriate capabilities to perform the tests?
• Does the chosen lab have the capability to use the same methods the supplier used on the CoA, or does it use modified or different methods? How does this affect the interpretation of the results?
• How much variance in results is acceptable? Is it enough that both results (i.e., the CoA result and the lab results) are within the specification limit, or are the criteria more stringent?
• How many distinct lots are needed to test before a brand feels confident it can rely upon the supplier’s CoA to be accurate and lot-representative? The cGMPs give no particular guidance for the number of lots needed to test in order to qualify the supplier or material; it may vary according to the risks associated with a particular raw material, and prior experience with the supplier’s reliability for other CoAs already qualified.
• How frequently will the supplier’s CoA need to be requalified? This is based on how frequently the material is ordered and other risk factors, but again, this interval is not prescribed by the cGMPs [21 CFR 111.75(a)(2)(ii)(D)].
• What documentation needs to be made and kept for the qualification? [21 CFR 111.75(a)(2)(ii)(C)].
Finally, a brand must ensure the documentation setting forth the basis for qualification and requalification of the supplier of a component, and the actual test results for each supplier, are reviewed and approved by the QC unit [21 CFR 111.75(a)(2)(ii)(E)].
It’s important that executive management supports the considerable effort and quality assurance (QA) resources required for a successful raw material qualification program. In terms of ensuring the integrity of the supply chain, firms that have robust raw material qualification programs are less likely to receive subpar ingredients because their suppliers know their test results will be subject to regular scrutiny and confirmation. In the case of unreliable suppliers that cannot be qualified, a brand will be able to quickly identify and remove them from the supply chain.
Marian Boardley is an independent consultant who manages projects for dietary supplement manufacturers and distributors. She helps clients in the food, drug and dietary supplement industries to implement compliance with dietary supplement, food and other cGMPs (current good manufacturing practices). She regularly trains staff to be ready for FDA inspections, and also writes documentation for quality control (QC), laboratory and manufacturing operations. Boardley was born in Yorkshire, England, and is now a U.S. citizen residing on the Colorado Plateau.