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18 March/April 2021 Tablets & Capsules Controlling the atmosphere to minimize instability Many consumers regularly take dietary supplements to improve their health and wellbeing, but such habits can be quickly broken by a negative experience. Omega-3 fatty acid supplementation in the form of fish oil (or algal oil for vegetarians) is common for both adults and children. Omega-3 fatty acids are composed of alpha-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA), all of which are considered essential fatty acids integral to many critical functions [1]. Inconveniently, omega-3 fatty acids are prone to releas- ing a fishy, rancid smell when exposed to and degraded by oxygen or light; even the slightest amount of degradation can result in the unpleasant odor. Children in particular are sensitive to tastes and smells, so such degradation is problematic. Omega-3 consumption is also associated with "fishy burps," which can occur after swallowing the supple- ment in capsule form. Such an experience is unwelcome, particularly as many consumers dislike swallowing large capsules in the first place. Manufacturers can avoid the occurrence of these unpleas- ant experiences by producing omega-3 supplements in a user-friendly dosage form. ODGs packaged in a small sachet provide a more user-friendly experience for the consumer, but they also represent a novel challenge for manufacturers navigating how to minimize degradation across a range of product forms. Controlling the manufacturing atmosphere is key to improving the stability of omega-3 ODGs. In an approach known as atmosphere filling, oxygen-sensitive APIs, such as omega-3s, are manufactured in an inert, nitrogen-filled atmosphere free from oxygen. Atmosphere filling is an established method that significantly increases omega-3 stability and creates a product with an improved shelf life more suitable for the market. A stability study at pharmaceutical standards (36 months at long-term conditions of 25°C/60% relative humidity (RH), 12 months at intermediate conditions of 30°C/65% RH, and 6 months at accelerated conditions of 40°C/75% RH) was conducted with an ODG containing omega-3 acids (sum of EPA and DHA: 100 milligrams) manufactured using inert atmosphere filling. The study showed that the product was stable under all conditions over the entire length of the investigated time span. In contrast, the same product frequently; specifically, they must test one batch of every product made for stability every year. If any tested prod- ucts fall out of specification, the company must immedi- ately notify regulatory bodies and evaluate the problem to determine the likelihood of any safety issues. Further batches may be recalled if product quality is deemed to be of sufficient concern. A company that has experienced a recall event will suf- fer financial and reputational damage. Immediate costs will result from lost sales of the recalled product as well as from the recall process itself, which includes costs for logistics, destruction of the recalled batch, and labor. In the long term, bad publicity will result in further lost sales as distrusting customers seek alternative products and doctors become reluctant to prescribe the recalled brand. Additional long- term costs may result if the company decides to switch to an alternative outsourcing partner for manufacturing. Ultimately, extending a product's shelf life is a way to gain a competitive advantage. For practical reasons, a minimum shelf life of two years is required for solid-dose medicines and dietary supplements. However, marketing departments are increasingly seeking shelf lives of three years or longer. For both medicinal and dietary supplement products, logistics, distribution, sales, and retail are all easier to manage when the product has a longer shelf life. Increasing stringency even in the absence of safety risk The need to test for and measure degradation products and impurities that may compromise product safety or efficacy is unquestionable. For instance, some degradation products resulting from poor stability may be associated with detrimental effects and should, therefore, be limited. However, not all degradation products are regulated using the same rationale. Manufacturers are required to specify and limit the amounts of all degradation products pres- ent—even those that don't pose a safety risk. For exam- ple, the degradation products of caffeine are harmless and exist naturally in the cups of coffee that people consume constantly on a global scale. However, for an oral dosage product that incorporates caffeine as an active ingredient, such as a pain reliever with aspirin, regulatory authorities tolerate only very small amounts of caffeine degradation products despite the absence of a safety risk. If tightening regulatory guidelines are any indication, stability is likely to become a more important consideration in the future. Regulatory bodies are becoming less tolerant of impurities and degradation products, even in well-estab- lished products such as aspirin, where manufacturing meth- ods might be assumed to be fixed. Consequently, regulators often ask companies to tighten their acceptance criteria for impurities when evaluating new product registrations. Addressing such requirements requires significant time and resources and can be a source of frustration when the rules seem irrational or ambiguous. To minimize impurities and meet strict requirements, manufacturers must establish even more sensitive and specific analytical tests, which create additional analytical challenges. Atmosphere filling is an established method that significantly increases omega-3 stability and creates a product with an improved shelf life more suitable for the market.