With the rise of e-commerce, global markets and specialization, the use of contract manufacturers has become the norm rather than the exception. Even the large multinational organizations rely upon a network of outside manufacturers as a means to streamline distribution, control quality and avoid the potential impact of a catastrophic event. Proper disaster planning through the implementation of business continuity plans universally embraces the use of several primary contract manufacturers in order to avoid a regional catastrophe, whether it be an earthquake, hurricane or a pandemic event.

The use of contract manufacturing for the production of dietary supplements creates unique challenges for both the brand owner and the independent contract manufacturer. A collaborative effort can minimize duplication of efforts and provide a clear plan for regulatory compliance.

Ingredient quality comes from ingredient control

We have all heard the familiar phrase “garbage in equals garbage out." When it comes to dietary supplements, the same can be said for the manufacturing process. In addition to “garbage," which can loosely be defined as contaminated ingredients, “unknown" or “unconfirmed" ingredients can also lead to an adulterated finished product. Production and process controls, commencing with 21 CFR 111 subpart E, begin with establishing specifications for each ingredient, and testing the incoming ingredients to confirm they meet the specifications.

To gain a better understanding of what is required, raw materials are defined as either a 1) component—any substance intended for use in the manufacture of a dietary supplement, including those that may not appear in the finished batch; 2) ingredient—any substance that is used in the manufacture of a dietary supplement that is intended to be present in the finished batch; or 3) dietary ingredient—a vitamin, mineral, herb, botanical, amino acid, concentrate, metabolite, constituent, extract or other substance used by people to supplement the diet by increasing the total dietary intake. This distinction is important when developing testing protocols for the ingredients and components used in manufacturing a dietary supplement.

Testing of incoming materials has significantly different requirements depending upon whether the material is a component or a dietary ingredient. All dietary ingredients must be tested or examined prior to use to verify identity. The only exception to this requirement is set forth in section 111.75(a)(1)(ii), which allows a petition to FDA for an exemption to the testing requirement. Ironically, this exemption only allows the use of an alternative test based upon accepted scientific rationale accompanied by the supporting data and information. So, for the vast majority of dietary ingredients, at least one test or examination must be conducted to verify its identity prior to use.

The identity of all other ingredients and components must also be confirmed prior to use; however, if the component is not a dietary ingredient, the certificate of analysis (CoA) from the ingredient supplier can be relied upon in lieu of additional testing if the following conditions are met:

In addition to identity testing, all components must be tested to determine if all other specifications are met. Section 111.70 requires specifications for purity, strength and composition, and limits of contamination be established and tested along with identity.

Production and process control

The basic foundation of compliance with 21 CFR 111 is the requirement of establishing proper production and process control systems. This starts with establishing proper specifications for all materials and implementing proper standard operating procedures (SOPs) for every step in the movement of materials through production. Incoming raw materials should be received into a specifically defined area for QC hold until sampled, tested and approved as meeting specifications. Implementation of a robust supplier qualification program can reduce testing costs and lessen the wait time between ingredient arrival and use in manufacturing. Once the QC hold has been released through testing and confirmation that the ingredients are within specification, the material can then be placed in inventory or moved directly to production.

Retaining samples

Proper QC procedures require representative samples of each unique lot of components, packaging and labels be collected, retained and identified. These samples must be retained for one year past the shelf life (if shelf-life dating is used) or two years from the date of distribution. The amount of the retained sample must be at least twice the quantity necessary for all tests to determine whether specifications are met. As an example, if lab procedures require a 100 g sample for testing, then at least a 200 g retained sample is required.

In addition to ingredient samples, it is necessary to retain samples of all containers or other materials that contact the dietary supplement, such as bottles, caps, blister packs, etc., as well as product labels. These samples should be retained as per the recommended time period.

The proper handling of incoming raw materials is the first step in the overall manufacturing system. Working with a contract manufacturer to follow proper procedures for ingredient handling as well as in-process manufacturing procedures will provide the proper foundation for continued compliance with FDA regulations.

Robert Danko, Esq., is a California dietary supplement lawyer who concentrates his practice in the area of GMP (good manufacturing practice) regulations and FDA compliance. With decades of experience representing food and beverage manufacturers, Danko has developed an expertise in dietary supplement law and in particular, GMP compliance. He brings valuable and timely legal expertise in GMP issues to Collins, McDonald & Gann (supplementcounsel.com) clients to help prepare for FDA inspections and avoid potential GMP failures.