US Dietary Supplement cGMPs and Ingredient Supplier Qualification
By Andrew Shao, PhD
Editor’s Note: In 2006, a group of dietary supplement industry trade associations formed the SIDI (Standardized Information on Dietary Ingredients) Working Group to help streamline communications among suppliers and customers. The efforts of the Working Group have since expanded to address the broader issue of supplier qualification, a requirement in the dietary supplement current Good Manufacturing Practices (cGMPs) regulation and a potentially critical element for the prevention of supply chain failures. We invited Andrew Shao, PhD, of the Council for Responsible Nutrition, a leading industry trade association, to explain this initiative and its current status.
Published by the US Food and Drug Administration (FDA) in June, 2007, cGMPs for dietary supplements (21 CFR Part 111) are now mandatory for all firms that manufacture, package, label, or hold dietary supplements for sale in the US, including foreign manufacturers who ship product to the US. Ingredient supplier qualification remains one of the most critical, yet least understood, aspects of the regulation. The increasing global supply chain and multiple instances of supply chain failures that have led to adverse consequences have elevated the need for proper supplier qualification across all FDA-regulated industries. Although defined in the regulation, its interpretation and FDA’s future enforcement of dietary supplement supplier qualification remain unclear, and there is little agreement on what constitutes industry best practices. Following the precedent set by other FDA-regulated industries, several responsible parties in the dietary supplement industry have formed a consortium to address the knowledge and practice gaps regarding supplier qualification.
The group has developed a series of voluntary guidelines to assist ingredient suppliers and dietary supplement manufacturers with the qualification process. These guidelines, some of which are still under development, are intended to serve as tools or templates on which a firm’s own qualification program or standard operating procedure(s) can be based. Those developing the initiative hope that these guidelines will serve as the basis for future FDA guidance or rulemaking, should the need arise.
Failures in the Global Supply Chain
In the past decade there have been numerous incidents and outbreaks in various FDA-regulated industries related to contamination or adulteration of material along the supply chain. The drug industry has experienced contaminated heparin,1 and glycerin contaminated with diethylene glycol in cough syrup2 and toothpaste;3 the food industry has experienced intentional adulteration with melamine4 and unintentional contamination by salmonella,5 all of which were linked to numerous deaths. While the dietary supplements industry has yet to be the source of a widespread outbreak associated with deaths, the US industry has historically suffered its share of accidental supply chain failures, ranging from contaminated tryptophan6 to contamination of plantain (Plantago ovata, Plantiginaceae) leaf with leaf of yellow foxglove (Digitalis lanata, Scrophulariaceae)7 to numerous reports of weight loss, bodybuilding, and male sexual enhancement products intentionally adulterated with active pharmaceutical ingredients (APIs) or analogs thereof.8,9,10,11 FDA leadership has stated repeatedly that the pharmaceutical spiking of products marketed as dietary supplements is the agency’s single greatest concern regarding dietary supplements.12 The aforementioned incidents all stemmed from supply chain failures. Somewhere in the process a vendor, supplier, or distributor was not properly qualified and/or failed to properly qualify the material being sourced.
US Dietary Supplement cGMPs Part 111.75
For dietary supplements, the requirement for supplier qualification is isolated to a small section of the GMP regulation. Subpart E, § 111.75(a)(ii)(A) states that before a dietary supplement manufacturer uses a component (and after verifying the identity of all dietary ingredients), the manufacturer may rely on an ingredient supplier’s certificate of analysis (CoA) to determine that all established specifications have been met, provided that:
[The “you” in the following list refers to the manufacturer] “(A) You first qualify the supplier by establishing the reliability of the supplier’s certificate of analysis through confirmation of the results of the supplier’s tests or examinations;
(B) The certificate of analysis includes a description of the test or examination method(s) used, limits of the test or examinations, and actual results of the tests or examinations;
(C) You maintain documentation of how you qualified the supplier;
(D) You periodically re-confirm the supplier’s certificate of analysis; and
(E) Your quality control personnel review and approve the documentation setting forth the basis for qualification (and re-qualification) of any supplier.”13
Comprehensive raw material testing can pose a substantial cost burden, and this provision is aimed at providing the basis to support reduced testing of incoming ingredients or components. Some may interpret the language in the cGMPs to mean that if reduced testing is not desired and that full testing (i.e., testing for all specifications) will be conducted of all incoming lots of raw material, then supplier qualification is not necessary. This may not be an appropriate interpretation, because testing alone may not be adequate to assure the quality of incoming ingredients. As pointed out in recent comments to the FDA, one cannot test for adulterants, economically motivated or otherwise, that one does not know exist, or for which no “scientifically valid” method(s) of testing exist. While a robust supplier qualification program cannot guarantee protection against adulterated ingredients or supply chain failures, when combined with a risk-based approach to ingredient testing, it can help minimize the likelihood and occurrence of problems. Indeed, in a recent letter addressed to the dietary supplement industry on the issue of products intentionally adulterated with APIs, FDA Commissioner Margaret Hamburg stressed the importance of supplier qualification, stating, “A strong program of qualifying your suppliers, testing incoming ingredients, and verifying the contents of finished products—all of which are required by the cGMP regulations—can help minimize those risks.”14 Such programs can be used to assess both the risks posed by a supplier and/or component and serve as the basis for supplier management (e.g., supply agreements, continuous improvement, etc.).15FDA has yet to issue any guidance related to maintenance of dietary supplement supply chain integrity. However, since 2009, Center for Food Safety and Applied Nutrition (CFSAN) officials at the FDA have been communicating the agency’s expectations to the supplement industry regarding dietary supplement ingredient supplier qualification at various trade shows and conferences. Officials have stressed the need for complete documentation of the process, involvement of quality control, and the need for the industry to be innovative in order to deal with the challenges of a global supply chain.16
As FDA implements the dietary supplement cGMPs, industry members are beginning to see agency inspectors focus on manufacturing firms’ supplier qualification programs, or lack thereof. Agency inspectors are now beginning to note the failure of Quality Control (QC) personnel to review and approve documentation serving as the basis for supplier qualification.16 While to date only about 100 large (500 or more employees) and medium (20 or more employees) companies have been inspected, the ensuing inspections of smaller firms (less than 20 employees) are expected to expose substantial deficiencies in supplier qualification.
Defining Supplier Qualification
Following the precedent set by the excipients (www.ipecamericas.org) and pharmaceutical (www.rx-360.org) industries, 3 dietary supplement industry trade associations* are in the process of creating a series of voluntary guideline documents aimed at helping US firms with supplier qualification (see www.crnusa.org/SIDI). The guidelines stress the principles of risk management based on International Conference on Harmonization (ICH) guidelines,17 as different ingredient suppliers and ingredients or components pose different levels of risk; this, in turn, drives the resource allocation dedicated to the qualification process. Risk may take different forms: It can include safety risks to the consumer and liability, financial, and/or supply disruption risks to the manufacturer. Table 1 provides examples of some general criteria or factors that may be used to assess risk. This list is not intended to be comprehensive, but merely illustrative of what criteria might be considered, and an individual firm’s experience may vary greatly. FDA’s diminished ability to inspect foreign manufacturers due to resource constraints renders these raw materials a higher risk. How manufacturing firms deal with or mitigate that risk depends on a combination of regulatory requirements, best practices, and business interests.
Qualification of botanical suppliers and/or ingredients poses some unique challenges. Many suppliers of botanical ingredients are located overseas, and botanical extracts can be difficult to qualify due to a lack of general familiarity with many of the materials, a lack of characterization and availability of reference standards, and appropriate and/or otherwise validated analytical methods. Furthermore, these extracts can be particularly prone to economically motivated adulteration through spiking with APIs, the addition of dyes (or other colorants used to foil colorimetric analytical methods), or substitution with cheaper species.18
The basic and most important aspects of supplier qualification appear in Table 2. The dietary supplement industry is diverse, with foreign and domestic ingredient suppliers, distributors, and contract manufacturers ranging in size from a handful of full-time employees to several thousand. The nature of ingredients and components varies greatly as well, from commodity vitamins and minerals, to excipients, to chemically complex botanical extracts. The resources available for regulatory compliance efforts, including supplier qualification, also vary greatly, as do business practices. Therefore, flexibility is a key factor in the development of these guidelines. The available and in-process voluntary guidelines are summarized in Table 3.
The most important considerations for supplier qualification fall under 4 primary areas: Supplier Capability/Audit Assessment, Certificate of Analysis Recommendations, Certificate of Analysis Verification, and Requalification and Disqualification (Table 2), as these pertain directly to the requirement listed in 21 CFR Section §111.75. The initial phase of qualification involves gathering and reviewing information, primarily in the form of documents. Typically, this pre-assessment is executed through the use of vendor questionnaires or paper audits, which are intended to probe, at a general level, a supplier’s manufacturing and quality systems and its adherence to applicable laws and regulations.
The dietary supplement industry has developed a voluntary guideline aimed at assisting ingredient or component suppliers with the compilation of this basic information for presentation to their customers in a clear, concise manner. Launched in 2006 and revised in 2008, the Standardized Information on Dietary Ingredients (SIDI™) protocol19 outlines the type and scope of information an ingredient supplier should provide to a dietary supplement manufacturer regarding its ingredient(s) to help fulfill the documentation needs of the manufacturer. The 41-page guideline includes sections that separately address botanical and non-botanical ingredients. By relying on the SIDI protocol to develop ingredient information packages or dossiers on a proactive basis, suppliers can provide the same basic information requested on questionnaires. Manufacturers frequently require that their own unique questionnaire be filled out, and each questionnaire can run from 50 to 100 pages in length. Some suppliers have teams of technical service representatives whose sole purpose is to fill out questionnaires, while manufacturers spend needless resources tracking down missing or incorrect information on returned questionnaires. Furthermore, the information provided in a vendor questionnaire is typically not subject to change control, so the accuracy of the information at any given time may be equivocal. Eliminating questionnaires and using SIDI-based dossiers in their place can result in significant cost savings for both suppliers and manufacturers. Some manufacturers have experienced a reduction in the time it takes to obtain this critical information from suppliers, from weeks using the questionnaire-based approach down to as low as a few hours using the SIDI protocol.20
The main elements of Supplier Capability/Audit Assessment include review of the suppliers’ quality management system and their compliance with applicable GMPs. An actual GMP audit of the suppliers’ facilities is necessary to provide a true sense of risk assessment, to determine the degree of GMP compliance, and the ability to meet customers’ needs. However, FDA CFSAN has stated only vaguely that it expects audits to be conducted and that it expects a full audit report to be on file (as opposed to a summary letter or statement from the auditor).17 Whether FDA will ultimately require actual audit information on all dietary supplement component suppliers used by a given dietary supplement manufacturer—and, if so, with what frequency—remains to be seen. Regardless of the specific requirements FDA may (or may not) impose, the approach should be consistent with the principles of risk management, with the higher-risk materials and suppliers receiving onsite audits more frequently.
Reputable, independent, third-party certifiers and auditors can effectively assist firms in assessing suppliers’ GMP compliance and thus in assessing (or mitigating) risk. In the US, the United States Pharmacopeia (USP; www.usp.org), NSF International (www.nsf.org), and the Natural Products Association (NPA; www.npainfo.org) all maintain well-recognized third-party certification programs that certify facilities and/or products, including suppliers and their ingredients. Independent third-party auditors can obtain audit information on an ingredient supplier’s facility at a fraction of the cost that a firm can incur in maintaining its own internal audit team. Collectively, third-party certifiers and auditors can help in risk assessment (GMP certified facilities from one of the aforementioned programs present lower risk) or risk mitigation (GMP deficiencies identified by a third-party auditor can lead to corrective actions) processes.
The CoA represents the official interface between the ingredient or component supplier and finished product manufacturer. According to FDA, at a minimum, “The certificate of analysis includes a description of the test or examination method(s) used, limits of the test or examinations, and actual results of the tests or examinations.”21 Adequate CoAs are needed to assure specifications are being met for all components as well as for contaminants, and confirmation of the test results and reliability of the CoA are specifically stated as supplier qualification requirements in the cGMP. However, the quality and content of ingredient CoAs vary greatly across the industry. To assist suppliers with the development of consistent CoAs containing the required and relevant information, a voluntary CoA Guideline was created.22 The purpose of the guideline is to provide recommendations for the preparation by suppliers, and appropriate use by their customers, of a CoA for dietary supplement components. Accompanying the guideline are example CoA templates for both botanical and non-botanical ingredients, given some of the unique specifications for botanicals. The goal is to standardize the content and format of CoAs for dietary supplement components, and to clearly define the roles and responsibilities for component suppliers, distributors, dietary supplement manufacturers, and other users who need to meet the dietary supplement cGMPs.
CoA verification is a requirement in the cGMP for those manufacturers who choose to rely on the CoA for all specifications except identity in lieu of full testing (i.e., testing each lot of incoming ingredients for all established specifications). This is a complex process that requires close communication between suppliers and manufacturers and can generally be divided into at least 2 phases: Pre-commercial and Commercial. Pre-commercial involves initial examination of the supplier’s CoA, with testing to confirm its general reliability. Commercial testing typically occurs after the manufacturer and supplier have agreed on or established specifications for the ingredient that meets the needs of the manufacturer for the ingredient’s intended use. Supplier-manufacturer communication may be necessary to establish the appropriate analytical methods that will ultimately be used in the Commercial phase of verification. The amount and scope of actual testing (i.e., number of lots tested, frequency of reverification, etc.) will depend on the risk assessment of the supplier (and ingredient) along with the performance of the supplier over the course of the relationship.
How, and with what frequency, suppliers are requalified should also be given ample consideration. The frequency of onsite facility audits, CoA reverification, and reevaluation of documentation are also highly correlated with the risk of the supplier and its past performance. It follows that the manner in which a given supplier manages change, or change control, becomes a critical aspect of the requalification process. Poor change control and change notification—particularly changes related to the manufacturing process or formulation—on the part of a supplier, can expose customers to unnecessary and burdensome enforcement actions and other liabilities. It is inevitable that some suppliers and ingredients will pose too high a risk to warrant inclusion in the dietary supplement product. Whether to cut ties with the supplier or consider some type or form of risk mitigation (i.e., working with the supplier to address deficiencies) is ultimately a business decision for the manufacturer. This decision requires ongoing collaboration among the firm’s different departments, including quality control, regulatory affairs, manufacturing/operations, procurement, and sales/marketing.
There are other considerations for supplier qualification that may not be required for cGMP compliance or assessing risk, but are still important for the ongoing supplier-manufacturer relationship. Also listed in Table 2, some of these considerations—or supplier management recommendations—include establishing appropriate supply and quality agreements, keeping thorough documentation and records, and striving for continuous improvement related to process and cost controls. Finally, there are best business practices to consider, although these are less likely to have a direct impact on the supplier performance or risk of the ingredient(s) under consideration. The business capabilities, financial stability, environmental stewardship, and labor and safety conditions of the supplier and its facilities can have an impact on its ability to perform and provide consistent, sustainable raw material. How well a supplier manages crises (e.g., if an important manufacturing facility is destroyed in a fire) can determine the continuity of its business. These are less critical, yet still important criteria to evaluate as they help assess the risk and reliability of the supplier.
Summary and Conclusion
The global supply chain has become more complex, with major outbreaks and adverse events resulting from breakdowns in the supply chain prompting the US government to propose new legislation concerning food and drug safety and importation. Some FDA-regulated industries have responded by developing recommendations or voluntary guidelines for supplier qualification. Some responsible elements of the US dietary supplement industry have begun the development and implementation of some voluntary supplier qualification initiatives. They should continue to address and implement minimum requirements, not wait for potential catastrophic failures in the supply chain that may prompt additional regulation from FDA or legislation from Congress—which would likely not be science- and risk-based, and possibly overly burdensome. For its part, these elements in the industry would welcome more open dialog and communication of its expectations for supplier qualification, continuing to be receptive to the exchange of ideas and information on approaches to supply chain qualification. In the end, consumers and policymakers will hold both FDA and industry accountable for supply chain failures.
Andrew Shao, PhD, is Senior Vice President of Scientific and Regulatory Affairs at the Council for Responsible Nutrition, a leading dietary supplement trade association in Washington, DC.
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* The Joint SIDI Working Group is comprised of representatives from the Consumer Healthcare Products Association (www.chpa-info.org), the Council for Responsible Nutrition (www.crnusa.org), and the United Natural Products Alliance (www.unpa.com), and member company representatives from each trade group, respectively. To inquire about the Working Group contact Andrew Shao at firstname.lastname@example.org.