Pluripotent stem cell-derived organoids represent a significant advance in modelling human brain development and disease in vitro. However, the application of organoids to understand and find new therapies for brain diseases has been impeded by the scarce reproducibility and scalability of these models, as well as the challenge of identifying reliable pathological phenotypes suitable as readouts in high-throughput drug screenings. We addressed these issues by establishing a highly standardised method that generates brain organoids with consistent morphology, including shape, size, structure, and cellular composition. Bright-field imaging, immunohistochemistry, and single-cell RNA-sequencing analysis of individual organoids showed remarkable organoid-to-organoid reproducibility across different organoids, cell lines and experimental batches. Over time, organoids generate a large collection of cell types resembling those seen in the developing human forebrain. This includes diverse types of progenitors, excitatory projection neurons, interneurons, late-born astrocytes and oligodendrocytes. We leveraged the reproducibility of this new organoid model to set up an automated system for the generation and high-throughput screening of brain organoids. By using this automated platform, we showed that forebrain organoids haploinsufficient for the epigenetic modifier KMT5B are associated with increased organoid size reflecting megalencephaly observed in patients. Finally, high-throughput screening of forebrain organoids treated with a library of FDA-approved epigenetic compounds revealed that individual drugs induce reproducible changes in organoid growth and development, further validating the reliability of this new brain organoid platform to identify disease phenotypes and for large-scale drug screenings. Overall, our work contributes to understand the role of epigenetic regulation during normal forebrain growth and development and paves the way to implement brain organoids into future drug discovery pipelines to identify potential therapies for neurodevelopmental disorders.