The probiotic supplement segment has experienced tremendous growth in the dietary supplement category in recent years. Due to the high demand of probiotics in various forms including tablets, capsules and sachets, new types of probiotic products with enhanced sensory experiences have been recently introduced to the market including gummies, liquid drops and chocolates. The demand for probiotics is expected to increase in the future. Because probiotics are live microorganisms with a complex taxonomic structure, there are some inherent challenges to their production and distribution. Though challenging, development of public standards for probiotics is important to help ensure quality and supply chain integrity through appropriate identification and enumeration methods for the ingredients, and by controlling for contaminants. Probiotics meeting the public standards from United States Pharmacopeial Convention (USP) will benefit consumers, regulatory agencies, researchers and manufacturers.
USP is an organization that brings together stakeholders and interested parties in support of its mission to protect public health and help ensure the quality, safety and benefit of all medicine, food and dietary supplements through development of public standards. USP develops standards using a unique, science-based, public process guided by its council of experts, who are from government, academia and industry. Once developed, USP standards are made available for public comment prior to finalization.
In early 2015, USP used this public process to develop and publish eight monographs of probiotic strains in the Food Chemical Codex (FCC). Included among these monographs were Lactobacillus acidophilus LA-14; Lactobacillus acidophilus NCFM; Lactobacillus rhamnosus HN001; Lactobacillus paracasei Lpc-37; Bifidobacterium animalis ssp. lactis HN019; Bifidobacterium animalis ssp. lactis Bi-07; Bifidobacterium animalis ssp. lactis Bl-04; and Bacillus coagulans GBI-30, 6086. These FCC monographs include description, identification, assay, specific tests and labelling requirement at the individual strain level.
USP is continuing to develop dietary supplement and FCC monographs, and standards for other probiotic strains. To that end, on Nov. 20, 2015, USP held a roundtable discussion to seek stakeholder feedback on the development of future USP standards for probiotics. About 40 stakeholders representing academia, regulatory agencies, ingredient manufacturers, finished product manufacturers and trade associations participated.
Main discussion topics at the meeting were: 1) the path forward for development of standards of dietary supplement ingredients and finished dosage forms for probiotics; 2) the potential need for reference standards such as genomic DNA for identification testing; 3) enumeration techniques and challenges with probiotic blends; and 4) development of best practices for the industry.
Stakeholders expressed different views. Some felt monographs should be developed at the strain level, while others felt development at the species level was appropriate. Since regulatory filings are regularly made at the strain level supported by information from clinical studies performed on specific strains, a monograph at the strain level was considered desirable as a link of the quality attributes to such regulatory filings. Regarding the question on the usefulness to have both types of monographs, species and strains, participants noted there is virtue in having species protocols to differentiate at that level (i.e., L. acidophillus vs. L. rhamnosus). There were proposals to address species level in guidelines or appendices and keep monographs for specific strains. Strain or species monographs could be used depending on the type of article in USP (ingredients defined at the strain level vs. finished dosage forms defined at the species level, naming suitable strains linked to labeling requirements). One challenge with species level standards is enumeration techniques, which are often different depending on the probiotic ingredient supplier.
The roundtable discussions noted that assay variabilities of the microbial enumeration test, based on enumeration of colony forming units (CFU), can be high, as much as 50 percent. Additionally, a microbiologist at USP mentioned typical variabilities of colony counting methods could be up to twofold, which is described in USP General Chapter 61. To overcome inherent challenges with enumeration tests, several stakeholders shared their experiences with flow cytometry, which counts live cells with much narrower assay variations. However, they cautioned that all cells counted by flow cytometry are not colony forming cells. Also, some of the stakeholders at the meeting noted that, due to the complexity of testing for identification enumeration and contaminants, most finished product manufacturers rely on third-party labs for testing on identification, contaminants and enumeration. Use of public standards from USP would promote transparency of the test methods adopted by the multiple labs throughout the supply chain.
Furthermore, to maintain compliance with 21 CFR 101.9 (g) (4), manufacturers add substantial overages to meet the requirement for 100-percent label claim through the end of shelf life in order to adjust for the rapid death rate of probiotic cells. Due to probiotics’ unique characteristics, industry practices for manufacturing, shipping and storage at controlled temperatures are crucial in complying with the FDA label claim requirement. In this regard, the Council for Responsible Nutrition (CRN) is working with industry stakeholders to publish a guideline for best practices for the probiotics industry, which may be available in 2016.
Regardless of whether label claims are made to the species or the strain level, compliance with cGMP (current good manufacturing practices) is mandatory. Industry stakeholders emphasized that manufacturing batch records as well as documents related to the probiotic ingredients used in a formulation should be easily traceable since the finished product testing may not include tests for the identity and strength of individual probiotic ingredients.
To assist manufacturers in cGMP compliance, USP offers the Dietary Supplement Verification Program (DSVP) and Dietary Ingredient Verification Program (DIVP) for third-party certification. Through this program, USP staff conducts audits of manufacturing facilities, procedures and records to ensure products and/or ingredients meet USP guidelines and standards, which are more stringent than FDA cGMP requirements.
Additionally, USP recently launched a new stand-alone Quality Systems GMP Audit Program for facilities that manufacture dietary supplements and dietary ingredients. Through this unique opportunity, USP offers manufacturers access to the most authoritative source for dietary supplement GMP audit standards. The stringent USP audit criteria go beyond the FDA cGMP requirements. The program also provides dietary supplement manufacturers with an important stepping stone toward USP’s respected verification program, and is yet another way USP is helping industry build consumer trust in dietary supplement products.
Probiotics are alive and growing. Now is the time to further global standardization for probiotic products. USP has initiated a process to communicate with stakeholders to develop public standards for probiotics. Many products in the dietary supplement market contain multiple species and strains of probiotics with functional claims on the label. Valuable input from stakeholders during the probiotic roundtable helped technical challenges to standardization. USP encourages manufacturers to participate in USP’s standard development processes to help create public standards, which can be an important resource for meeting GMP requirements. USP can help industry to ensure further compliance through its verification and quality systems GMP audit programs.
Seong-Jae (SJ) Yoo, Ph.D., is a scientific liaison-dietary supplements at United States Pharmacopeia (USP, usp.org) responsible for the development of quality standards for dietary supplements.