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Tablets & Capsules October 2014 32C forming units (CFUs) per gram to upwards of 1 trillion CFUs per gram. Some cultures are supplied in standardized concentrations, while the concentrations of others vary depending on how they were fermented. The physical den- sity of a specific culture may also vary by strain and by manufacturer. When restricted by volume limitations, as in the case of a capsule shell, it may be helpful to think of cell density in terms of cells per unit of volume. When volume limitations are not a major factor, as with sachets, cell den- sity may be calculated simply as cells per unit of weight. Overage In the language of probiotic manufacturing, "overage" is the number of live cells required in excess of the stated label claim to ensure the claim remains valid for the duration of the product's shelf-life. Factors that contribute to cell death include culture stability, water activity, package permeabil- ity, heat exposure, and expected/desired length of shelf-life. Failure to account for these factors will force you to increase overage, which drives up the amount of cell culture required in the formulation. The inherent stability of the live cells themselves is fundamentally strain-specific. The more stable the strain, the less overage required to obtain a minimum label claim. Less stable strains on the other hand require greater overage, which crowds the already limited volume within the dose. Because every microliter of space is valuable with ultra-potent probiotics, only the most stable strains are good candidates for use. Other ingredients Probiotic products generally require carriers and pro- cessing aids to facilitate powder processibility. Microcrystalline cellulose dried to very low water content is commonly used as a carrier for probiotic capsules. Among processing aids, silicon dioxide and magnesium stearate are favored for their effectiveness as powder-flow agents at relatively small usage levels. Any secondary actives (plant extracts, vitamins, minerals) must be tested to ensure that they have no antimicrobial properties or other deleterious effects on the living probiotic cultures. It is important that all added ingredients be kept as dry as possible—re-drying them if necessary to prevent them from diminishing the stability of the probiotics. Processibility The fixed volume of the capsule shell is a key limita- tion for probiotic capsules. The density of the powder blend and its ability to be compressed into a slug deter- mine the total fill weight of the capsule. In general, any product that exceeds 60 percent culture by weight should be tested in pilot studies using commercial machinery to determine feasibility. That said, there are products con- taining more than 80 percent culture by weight that suc- ceed, while others with much lower culture percentages fail, often due to extreme hygroscopicity or stickiness. Environmental control Many of the factors affecting the success of ultra- probiotics involve control over process conditions, in - cluding maintaining humidity within a narrow range, usu- ally less than 30 percent relative humidity (RH). Because the cultures are typically dried to water activity levels (A w ) of less than 0.100—and even as low as A w 0.003— they are hygroscopic and tend to absorb water readily. [Editor's note: For more information on water activity, see "Measuring water activity as a means to reduce microbial limit testing" in the October 2008 issue.] Exposure to RH exceeding 40 percent will quickly cause the powder to become sticky. The biggest pitfall to manufacturing probi- otic capsules is the buildup of sticky powder on the carrier segments, which leads to improper seating and closing of the capsule shells (photos). Therefore it's important to minimize bowl spillage and segment spillage during slug transfer from the bowl to the capsule body. Some manufac- turers use a dosing disc one size smaller than the capsule (e.g., a size 1 disc for a size 0 capsule) to avoid depositing powder on the rim of the lower carrier segments. Packaging concerns The moisture (or water) vapor transmission rate (MVTR or WVTR) is the single most important criterion for Accumulation of sticky powder on carrier segments (left) and tamping pins (right) complicates the manufacture of probiotic capsules. To avoid it, keep all ingredients dry and maintain a relative humidity below 30 percent.