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40 Pharmaceutical Technology ® Quality and Regulatory Sourcebook March eBook 2023 PharmTech.com viewpoint the safety of E171. This should be the basis for how global regulators assess the safety of E171 going for- ward because most global regulators look to JECFA for credible scientific safety assessments. Hopefully, the outcome of this JECFA review will impact the future of E171 use in both foods and pharmaceuticals in all regions, including the EU. Potential impact to pharmaceuticals: reformulation challenges and product withdrawals Upon banning E171 for food uses, the EC of fered a t h ree-yea r t i me per iod w it h i n wh ic h t he Eu- ropea n Med ici nes Agenc y (EM A), a longside t he ph a r m a i ndu s t r y, ca n a ssess t he fea sibi l it y of various TiO 2 alternatives and how a potential ban of TiO 2 may impact pharma products and patients (9). It is important to stress that currently there is no direct alternative that exists for the replacement of TiO 2 (E171). All the benefits that TiO 2 lends to a drug product, like inertness, opacity, and light protection, do not currently exist in any alternative material that can be easily substituted into a ready-made film coating color mixture or hard capsule shell for use in pharmaceutical products. Several TiO 2 free coat- ing products and capsule shells are available on the market, which may work in some applications, but there will t y pically be real challenges with using these systems, especially where a drug substance is light sensitive or where the color of the tablet core or capsule shell fill material is not white. Any EU ban on TiO 2 for pharmaceutical uses would cause significant impact to patient access to critically needed drug products across Europe. Currently, there are more than 91,000 approved human drug products and 800 veterinary medicines on the market in the EU containing TiO 2 , which would need to be reformulated if TiO 2 is banned in pharmaceutical products (10). The issue comes down to how 91,000 drug products can be reformulated without there being serious implications to availability and drug costs, especially if you under- stand what is involved in reformulating a drug prod- uct, running necessary studies, and getting approval by regulatory bodies for the change. Reformulation of these existing drug products is not simply a case of removing TiO 2 or substituting it with the next white pigment. Each drug product needs to be assessed individually; TiO 2 has some unique prop- erties that can't be easily replicated. To get anywhere close to the same level of opacity, multiple different excipients/food additives need to be used in combina- tion, and each one needs to be assessed for compatibil- ity, regulatory compliance, safety, availability, quality, and in the final product, manufacturability and stabil- ity would also need to be determined. A recent paper was published by members of the IQ Consortium that explains the difficulties in reformulation very well (11). In addition, because the reformulated drug prod- uct would be significantly different from a compo- sitional perspective, it may not even be possible to develop a reformulated dr ug product, which will perform equivalently to the existing drug product on the market used by millions of patients. The per- formance and the quality of the product may be ac- tually quite different. Although there is variation from company to com- pany, the overall estimated cost to the pharmaceu- tical industr y to reformulate all these products is around €32 billion (US$34 billion). Who will pay for this? Many companies indicate that for low-volume products, such as pediatric, geriatric, and orphan dr ugs, or products wit h old dossiers t hat are too complicated to change, they will simply withdraw the drug products from the European Market (10). This would leave millions of European patients without the drugs they desperately need for their health. There is also the question of how regulators like EMA would be able to deal with 91,000 post-approval change notifications if a ban were to be put in place for E171 in pharmaceuticals. How many additional rev iewers wou ld need to be h i red? W hat i mpact would this immense workload have on the approval timelines of new drugs essential for patient health? Su rely, new a nd gener ic-d r ug approva ls overa l l would be slowed down significantly due to resource constraints that would certainly occur. Therefore, pa- tients who might desperately need new drugs that are under development might have to wait to gain access to these drugs due to a situation caused by decisions not based on any real risks. If t here act ua l ly was a safet y concern t hat has been demonstrated, this would be an entirely dif- ferent conversation. However, this is not the case. EFSA and the EC have utilized poor quality studies on Nano TiO 2 grades that have little to do with the grades of TiO 2 (E171) that are actually used in foods and pharmaceuticals, to come to an extremely pre- cautionary decision that is not justified in the eyes of many highly qualified scientists around the world. Industry actions to incorporate a scientific perspective The International Pharmaceutical Excipients Council (IPEC) is working with the IQ Consortium and other global industry groups in a collaborative way to share information throughout the industry and develop plans for collecting and providing information to EMA and other global regulatory agencies related to the chal- lenges of trying to reformulate to a TiO 2 -free product due to the technical limitations of the alternatives. The European Federation of Pharmaceutical Indus- tries and Associations (EFPIA) has formed a working group who is also assessing the potential for use of