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18 Pharmaceutical Technology ® Trends in Formulation 2023 eBook PharmTech.com Drug De velopment a particular formulation and include population vari- ability. Moreover, PBPK models can help evaluate the fate of a formulation in different prandial states such as fasted vs fed conditions, in a pediatric vs adult gas- trointestinal (GI) tract, in subjects with achlorhydria, etc. PBPK models can also help assess and optimize the role of excipients on dr ug solubi lit y, dissolu- tion, and absorption, evaluate the salt selection and solid-state polymorphism, enabling formulations to be examined under in-vivo conditions without performing clinical studies. Biosimulation and formulation development A drug formulation involves combining the API with functional excipients and other inactives to enable absorption (bioavailability), improve stability, and optimize the final product form, resulting in a drug that is easy to administer, safe, and effective for pa- tients. It considers factors such as particle size, poly- morphism in solid state, solubility, and salt forms, by assessing the physicochemical properties of an API, excipient type and interactions, dosage strength, and manufacturing procedure. MIFD delivers benefits across the drug develop- ment cycle (Figure 1), from early Phase I formulation development and modeling the assessment of salts, polymor phs, excipients, prodr ugs, or amor phous solid dispersions—to demonst rat ing v ir t ua l bio- equivalence (VBE) for formulation bridging and a biowaiver for scale-up and post-approval changes (SUPAC). Specific applications include evaluating the impact of changing and optimizing a formula- tion, SUPAC, or optimizing an extended release (ER) form for an existing immediate release (IR) dr ug product. MIFD can also be used to enable clinically relevant dissolution specs and/or discriminator y dissolution method development; define safe space; inform 505(b) (2) applications for expansion of ap- proved drug products; establish bioequivalence for complex generic dr ugs; and develop pediatric for- mulation bridging strategies. Speci f ic to t h is topic, t he mecha n ist ic, physio- logically based Advanced Dissolution, Absorption and Metabolism (ADAM) model helps formulation scientists predict the variability in human oral drug absorption using physiochemical and in vitro drug (product) data. The ADAM model can simulate a va- riety of orally administered formulations: solutions, suspensions, and IR tablets through to single unit (monoliths) and dispersible dosage forms (in other words gastro-retentive, enteric coated tablets and granules, controlled release (CR) monoliths, and CR dispersions) that release the API over time. MIFD is applied during the development of novel drugs, which of ten involves multiple formulation iterat ions f rom Phase I to com mercia lizat ion, as c l i n ic a l k n o w le d g e i n e n r ic h e d . F or e x a m ple , Phase I formulations may be simpler, such as pow- der-i n-capsu le (PIC), t ha n du r i ng Pha se I I when the more refined formulations with suitable salts and solid states are evaluated. As the target dose a nd dosage st reng t hs a re ident i f ied i n Phase III, f u r t her for mu lat ion opt i m i z at ion i s per for med to en h a nce ea se of u se a nd pat ient compl i a nce. T he n a t t he c om me r c i a l i z a t ion s t a ge , f u r t he r scale up, manufacturabilit y and process controls a re set up, lead i ng to f u r t her ref i nement of t he formulation. At each of these stages, comparison of new formulations wit h t he prior formulations is t y pica l ly requ i red. Su f f icient ly ver i f ied PBPK models ca n help w it h t hose eva luat ions w it hout r e q u i r i n g d e d ic a t e d c l i n ic a l r e l a t i ve bio av a i l- abi lit y (BA) or BE st udies to be per formed. MIFD can a lso help with identif ication and assessment of p e d i at r ic f or mu l at ion s to s upp or t Pe d i at r ic Investigation Plans (PIPs). Many post-approval manufacturing changes to marketed drugs must be reported to FDA and other reg ulator y agencies, f requent ly w it h t he need to demonstrate BE based on changes to t he product or process. Manufacturing site changes, such as a move to a different site or different area within the same site (non-sterile products), and site changes for sterile products, require this t ype of reporting. Our first case study is focused on the impact of c h a ng i ng m a nu f ac t u r i ng sites a nd t he requ i re- ment to demonstrate BE bet ween products of the 'same' formulation. By integrating and quantifying information about the drug, disease, how the drug affects the human body and how the body responds to the drug biosimulation (MIFD) optimizes decision-making.