On September 6, the FDA submitted for comment a Draft Guidance entitled, “Policy Regarding Quantitative Labeling of Dietary Supplements Containing Live Microbials: Guidance for Industry.” The document addresses how to list the quantity of probiotic ingredients on dietary supplement product labels. Current FDA regulations require listing dietary ingredients, including probiotics, by metric weight such as milligrams. The World Health Organization (WHO) has established a definition of probiotics as, “live microorganisms which, when consumed in adequate amounts, confer a health benefit on the host.” The FDA defines a live microbial as, “a single-celled prokaryotic or eukaryotic microorganism that is intended to be viable at the point of ingestion.” Therefore, it is problematic to indicate live microbials by metric weight because it does not provide any indication of therapeutic efficacy or strength of the probiotic ingredient(s).

The International Probiotics Association (IPA) attempted to reconcile this issue in January 2016 by submitting a Citizen Petition asking the FDA to amend the existing regulation to require listing the quantitative number of probiotics in dietary supplements on product labels as Colony Forming Units (CFU) instead of milligrams. The petition cited CFUs as the best available metric for indicating the number of viable cells. The IPA pointed out that the FDA has previously allowed CFUs as a measurement metric for New Dietary Ingredient (NDI) notifications as well as applications for Generally Regarded as Safe (GRAS) designation. 

   IPA Petition Gains Support

Many Probiotic Industry groups and stakeholders supported the Citizen Petition including IPA Europe, the International Scientific Association for Probiotics and Prebiotics (ISAPP), and the Council for Responsible Nutrition (CRN). Comments submitted overwhelmingly agreed with the IPA Petition and recommended changing the regulation. In 2017, CRN partnered with IPA to produce non-binding Best Practices Guidelines for Probiotics manufacturers, recommending to their constituents that in addition to complying with applicable labeling regulations requiring listing weight in milligrams, they should also indicate the level of probiotics in CFUs on product labels.

Some industry stakeholders, however, did not support the IPA petition. Those opposed contend that CFUs are not an accurate indicator of viable organisms and may provide misleading information to consumers. Since probiotics entail numerous strains of microorganisms and the established therapeutic value and safe serving size associated with these strains varies greatly, listing CFUs may give consumers a false sense of “more is better” when viewing the numbers on the label. Also, CFUs are determined by counting culturable bacteria on microbiological growth media and do not account for viable but not culturable (VBNC) organisms nor inactive organisms that may re-activate when entering the gastrointestinal tract, where conditions are more conducive to growth and replication.

    Flow Cytometry as Emerging Solution

Many opposed to the Petition believe while CFU counts provide a better measure than metric weight, they do not offer consumers an accurate level of probiotic dietary ingredients and therefore may cause confusion.  They point to other available methods capable of potentially achieving a more accurate determination of the viable organisms without the limitations of cultural CFU methods. One of these methods is Flow Cytometry. Proponents of Flow Cytometry believe it is a superior technology for accurately enumerating probiotics since it can measure multiple bacterial parameters including DNA replication, metabolic activity, and membrane integrity and can capture VBNCs. As opposed to cultural CFU methods which are limited to specific bacteria families, Flow Cytometry can count cells of several species in a mixed population without the need for multiple selective growth media.  Flow Cytometry is much faster to results than CFU cultural methods, can be adapted to measure probiotic bacteria in complex matrices, and can be scaled up to run in high-throughput capacities.

Using Flow Cytometry, scientists can measure probiotics in Active Fluorescent Units (AFU) and/or Total Fluorescent Units (TFU) which some believe provide a much more accurate snapshot of viable microorganisms than CFUs.

However, as previously mentioned, the FDA has allowed CFUs as the measure of dosage strength for New Dietary Ingredient (NDI) notifications and Generally Regarded as Safe (GRAS) designations. Also, clinical studies have utilized CFUs to determine the effective dose of probiotic ingredients needed to accomplish the therapeutic result. Therefore, if the preferred metric changes to AFUs or TFUs, legacy data would be null and void because CFUs cannot be converted to AFUs or TFUs.  There would be no way of knowing what dosage in AFUs was safe or clinically effective without repeating all the research and inflicting an unmeasurable financial burden on the probiotics industry. Critics also indicate Flow Cytometry’s effectiveness on older products and certain matrices such as fatty oils remains in question.

FDA Rejects Petition Offers Compromise

After considering all the comments submitted and reviewing additional information, the FDA produced the Draft Guidance to both provide the current regulatory standing on the subject and serve as a rejection of the IPA’s Citizen Petition. The Guidance stops short of mandating CFUs on labels, but allows firms to declare, in the Supplement Facts label of products containing probiotics, the number of live microbials in CFUs, in addition to the quantitative amount by weight required by regulation, provided they meet the following conditions:

• The quantity is first listed in terms of weight;
• The quantity in CFUs is expressed in a manner that is clearly separate and readily distinguishable from the weight, e.g., as a parenthetical or in a subset line;
• The declaration of quantity in CFUs is formatted in clear terms that can easily be understood by a common reader, e.g., 10 billion or 300* (where the unit that “*” is intended to represent, such as million or billion, is a typical measurement of CFUs and is clearly indicated elsewhere in the Supplement Facts label);
• The declaration of quantity in CFUs is accurate and not misleading, and does not render misleading other aspects of the Supplement Facts label, or other aspects of the product label;
• The declaration of quantity in CFUs measures only live microbial ingredients and does not include inactive, dead, or nonviable organisms;
• Live microbial dietary ingredients in a proprietary blend are listed in descending order of predominance by weight; and
• The product label otherwise complies with all applicable laws and regulations.

The Future of Probiotic Enumeration

According to the Draft Guidance, “While (the FDA) currently believes that CFUs provide a useful description of the quantity of live microbial dietary ingredients, we are aware that researchers are currently evaluating other methods and units of measure for live microbial dietary ingredients and that such alternative methods have the potential to more accurately and more efficiently quantify the number of viable cells in a product at a future time.  Therefore, at this time, we intend to continue monitoring the development of new technologies and their potential impact on the use of other units of measure on the Supplement Facts label before deciding whether to engage in rulemaking to revise the Supplement Facts regulations.”

Another reason the FDA gives for stopping short of mandating CFUs on labels is dietary supplement manufacturers are already in the process of preparing new labels to comply with the Nutrition and Supplement Facts Label Final Rule, effective on either January 1, 2020, or January 1, 2021, depending on company size. Requiring a change to CFUs now and then changing the requirement to TFUs, AFUs, or another unit of measure soon after would require relabeling and inflict an economic burden on manufacturers.  The FDA prefers to wait until they have determined the best technology for enumerating viable microorganisms.

The FDA is accepting comments on the Draft Guidance until November 6, 2018, and will make any changes and release a Final Guidance at a later date.