October 12, 2020
Sometimes component blends of a product are prepared for inclusion at a further stage of manufacture.
Proprietary blends are not considered premixes, as they are added as a single entity for labeling purposes.
Premixes can fall under a variety of scenarios regarding the regulatory burden for testing ingredients.
The dietary supplement industry includes a wide variety of compositions, ranging from single-entity supplements to others containing a plethora of ingredients. During production, it is sometimes advantageous to prepare premixes (blends of some of the components of the product) to be set aside for inclusion at a further stage of manufacture. These are true premixes in the product development sense.
Other blends of materials are frequently identified as premixes but, depending on the source, may more rightly be considered actual components—dietary ingredients—from a regulatory perspective; let’s put aside the issue of when “flavors” are actually determined to be ingredient blends and not actual permitted flavors. Each has its own regulatory obligations associated.
Lastly, a word about proprietary blends. These, in the original intent of the efforts for this inclusion in the finalization of labeling regulations (21 CFR 101.36) in 1997 that established “proprietary blends” at 101.26(c), are not premixes. They were intended to be specific blends of materials designed to be included in dietary supplement finished products added as a single entity for labeling purposes. What’s occurring today with these is a vastly different picture and subject to a much lengthier discussion. For now, let’s look at the two variants for premixes identified here and the regulatory ramifications of each.
During formulation development, improvements or best ways of doing things are understood and/or learned. For example, it is often necessary to blend certain components that are present in the formula in very small quantities with other components on a smaller scale before including the whole thing into the full batch. This affords better dispersion and homogeneity of the smallest component throughout the batch. Other instances involve coating some of the components before inclusion in the complete batch. In either event, the regulatory requirements include the need to establish in-process specifications since the creation of the premix is a point in the manufacturing process where “control is necessary” [21 CFR 111.70(c)(1)] and monitor these points and determine whether these specifications are met [21 CFR §111.75(b)].
The black-and-white requirement would be to test the premix before use to ensure it is composed of the appropriate components at the appropriate levels. This requirement may not be universally applied in the world of premixes. This is additionally necessary since part of the requirements for exempting finished goods specifications from testing includes the results of testing at the component and in-process steps of manufacture [21CFR §111.75(d)(1)]. Surprise. The testing requirements exist within the regulations and such testing is further necessary in order to avail oneself of the finished goods testing exemption offered.
The second premix scenario to consider is a purchased premix. Manufacturers often incorporate ready-blended components for use in their formulations. The regulatory burden for testing here shifts a bit. Since the material received (the blend) is a component, it must be tested for identification, at a minimum. If the blend is terribly complex, what does one do to test it? Does the supplier even provide adequate test information to verify? More importantly, what does one do to affirm the composition of the individual components used in the blend ensure compliance? This is additive to the in-process testing necessary (although dependent upon the manner in which the premix is added to the manufacturing process), and it may not be considered a point where control is absolutely necessary, but the in-process monitoring testing must still occur.
The open questions regarding the use of these premixes require answering in the most compliant manner possible. The requirements are clear enough, the execution is the challenge. Thus, in this instance, the testing of the premix upon arrival must be complete to assure that each of the purported ingredients is present, along with any potencies anticipated from the premix itself. This is becoming a key focus point of regulatory inspections. The demonstration of the presence of each listed dietary ingredient is now the expectation of FDA.
The last requirement of the regulations is set all throughout Part 111. The requirement is to document each determination made regarding selection of test methods [21 CFR §111.320] and how any determinations were made concerning exemption of any specification from testing [21 CFR §111.70(c)(2); 111.75(a)(2); 111.75(d)]. Too often overlooked are these documentation requirements. At its present rate of inspection evaluation, compliance with the documentation aspects and requirements of the regulations is of great interest to FDA. Ensure that the documentation of the activities performed and decisions made is compiled, reviewed and signed by the quality unit operation. This avoids a raft of challenges when inspection time comes.
Another important consideration involves the opportunity to petition for a premix and the level of testing required to be considered as a component by the manufacturer of the dietary supplement. These petitions are not simple requests and require substantial presentation of the scientific rationale with supporting data and information regarding the proposed requirement to test [21 CFR §111.75(a)(1)(ii)].
When it comes to premixes and their use, there are unevenly enforced aspects of the regulations concerning these items by the federal agencies. No direct provision within the regulations exists to either emphasize or exempt such items from the full implementation of the regulations. It remains incumbent on the users of these premixes to apply all aspects of the regulatory requirements noted before authorizing a lot of the premix to be used in manufacturing. This does involve more testing than is typically employed, but this is a matter of increasing interest regarding compliance on the part of FDA.
The means to nearly all the challenges are available, with cost. The challenge is in accurately assessing one’s relationship with premixes, what they require and what can be done to perform in the most efficient, compliant fashion possible. This includes the correct use of the exemptions allowed and proper documentation. Compliance includes correct adherence to the requirements, performance and documentation associated with use of these products.
As chief operating officer, Jim Lassiter oversees all consulting operations at REJIMUS. He has more than four decades of experience in quality control (QC), and government and regulatory affairs throughout the pharmaceutical, dietary supplement and natural product industries
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