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Pharmaceutical Technology REGULATORY SOURCEBOOK SEPTEMBER 2021 9 to remove TiO 2 could take up to 10 years with a significant cost, and potentially create differences between products for the European Union and the rest of the world (2). Alternatives Some supplement and drug manufacturers and their suppliers have, however, considered alterna- tives. In nutraceuticals and food supplements, con- sumer demand for "clean label" ingredients (e.g., "titanium dioxide free") is a driver for development of potential replacements. "Although no functionally direct replacement exists for TiO 2 when used as an opacifier or pig- ment, Colorcon has developed alternative film coating systems that provide similar functional- ity and appearance," says Kelly Boyer, vice-pres- ident of Film Coatings, Colorcon. The company has been developing alternatives for several years and has been using new methods to characterize whiteness and opacity in use. "We've screened 50 new materials and evaluated over 250 differ- ent combinations to identify the best TiO 2 free coating possible. The use of calcium carbon- ate as an opacifier is currently the most effec- tive replacement for titanium dioxide in coating formulations," says Boyer. Chandan Kaiwar, product manager for coatings at Kerry, suggests that there are several alterna- tives to TiO 2 ; some alternatives that could be con- sidered and show promise are calcium carbonate, tricalcium phosphate, isomalt, and other minerals in combination. "The best alternative to use will be very much dependent on the application itself, and the desired properties of the finished drug product," says Kaiwar. He explains that although alternatives have good opacifying and whitening characteristics, they are unlikely to be a "drop in" equivalent, and adjustments to the formulation, processing, and costs of the final formulation may be needed. "[When reformulating,] formulators will obviously try to keep any changes to an ap- proved drug product to the absolute minimum, but some will be unavoidable. Careful consideration to effects of the change of the formulation itself and the processing conditions needed, as a result, are key to ensure the TiO 2 replacement does not af- fect the drug product itself (i.e., safety, dissolution, stability, and efficacy). Regulatory considerations of the reformulated drug product must also be paramount when a coating formulation change is made. Kerry's SheffCoat TF [titanium free] family of coatings provides formulators with several op- tions depending on their application," says Kaiwar. Colorcon has conducted stability and functional testing for film coating systems. "Opadry TF [tita- nium-dioxide free] coatings have been thoroughly tested for opacity and stability using typical tablet cores, such as model actives for pharmaceutical use. It's important to ensure the coating maintains stability of the active ingredients in the core and there is no bleed through or appearance of dark spots through the coating. Good environmental protection is also essential as tablets are often re- moved from their original packaging and put into secondary containers such as pill boxes, then kept in a warm, humid environment. Stability is key to maintaining tablet integrity and protecting the active ingredients," notes Boyer. References 1. EFSA, "Titanium Dioxide: E171 No Longer Considered Safe When Used as a Food Additive," Press Release, May 6. 2021. 2. T. Eberwein, "Titanium Dioxide Declared Unsafe in Food Products, Raising Concerns for Drug Manufacturers," pharmalex.com, Aug. 4, 2021. PT