Orforglipron

Hyderabad: Having dominated the global biopharma innovation agenda over the past few decades, the complex science of peptides and oligonucleotides is gradually making inroads into Indian laboratories led by the unfolding contract research arms and the looming patent-cliffs over blockbuster brands opening the door for Indian players with similar biologics. However, unlike small molecules, the regulatory landscape for large molecule-based drugs is far more intricate. It involves multiple checkpoints owing to their structural complexity, diverse analytical standards, immunogenic potential, and challenges in maintaining production consistency. To delve into these challenges, the Hyderabad chapter of the ET Pharma Biomolecule Workshop & Connect convened a panel discussion titled “Navigating the Regulatory Maze: The Challenges of Peptides & Oligonucleotide Approvals.” Subject experts and innovators shared insights on the scientific and regulatory journey for these next-generation therapeutics. The panelists for the session included Dr Gopal Vaidyanathan, Senior Vice President – Analytical R&D and Development Quality Assurance, Natco Pharma, Dr Chandra Shekar, SVP, Head of R&D, Hetero Drugs, Dr Suresh Varma Penumathsa, Director and Head – Analytical, Preclinical and Clinical R&D, Biological E. Limited, Dr Manoj Metta, Principal Scientist, US Pharmacopeia. The moderators for the panel Dr. Ranjan Chakrabarti, Consultant, and Vikas Dandekar, Editor, ET Pharma Central Checkpoints Immunogenicity of peptides a major hurdle for innovators and is also being closely monitored by the regulators Dr Penumathsa suggests, right from the beginning of the development one should track the aggregation pattern, and there are several ways such as like Thioflavin T assay to analyse and address them in the initial stage itself. In terms of impurity profiling Dr Vaidyanathan said unlike the small molecules which have clear identification and qualification thresholds, peptides are drive by comparability study some of the new technologies like liquid chromatography, mass spectrometry have helped to keep the impurities level below 0.1 per cent. For drugs like GLP-1 which have longer amino acid chains ensuring a GMP compliant mass spec in each plant requires a huge cost, secondly re-qualification of a peptide is not possible, he added On part of regulators Dr Metta Principal Scientist, US Pharmacopeia flags that though agencies like FDA, EMA have published guidelines for both innovators and reference listed drugs, but due to lack of standards and analytical reference material companies still encounter challenges in selecting methods for adaptive immunity, innate immunity, product specific impurities, process specific impurities, implementing the emergency platform etc. To fill this void the official informed that USP is working on a comprehensive version of guidelines around less than 1000 chapters that will provide precise guidance and system suitability criteria. Manufacturing Constraints Dr Chandrashekar shared that for recombinant peptides the evidence of proving that it is nonimmunogenic requires a case by case analysis and depends upon the strategy of individual organisation to invest in that area. Whereas synthetic peptides (RLD) are straightforward cases and require testing only specific impurities of concern in immunogenicity. Most generics manufacturers in India are opting the synthetic route, where there is some scope for greater automation and looking at the product lifecycle these peptides may undergo drug transformation in the coming years, he added. Besides this experts also opined that in peptide production both API and finished drug manufacturers had to make an additional spending for capacity expansion and that increment gets reflected on the final product price. “The guidelines for manufacturing peptides have several grey areas and incases of drugs with more than 20 amino acid sequences the selection of critical quality attributes is highly important. Currently USP provides guidance over five peptides but for the rest manufacturers and the scrutinizer has to take onus of selecting the appropriate approach" Dr Metta said. Besides this for impurities evaluation manufacturers encounter another dilemma in implementing the orthogonality method or the supplementing method and how many how many of them is required to file for a NDA submission The serendipity of time is offering a lucrative opportunity to join the peptide buzz and Dr Vaidyanathan suggest, “Before Lilly’s small molecule-based late-stage candidate (orforglipron) hits the market, the GLP-1 peptide category is a money making time for the Indian generic players.” In the long term, he further noted, if a company can master the scale of recombinant peptides in line with Indian price points, it will be “sitting on a gold mine.” By Abhijeet Singh ,