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Adapting Continuous Flow to Peptide Manufacture
Design and Solid-Phase Synthesis of Muramyl Dipeptide (MDP) Surrogates as NOD2 Signalling Activating Agents
There are significant differences in the manufacturing and testing requirements between supplying drug for clinical trials and registering a drug for market access. For small to mid size companies, these development expenses are often pushed to late stages when the risk of failure in clinical studies is lower. We present the results of our efforts to optimize and characterise our drug substance manufacturing process to support market registration and commercial production.
Continuous flow is an emerging technology which has many benefits in terms of reduced cost and increased safety. However, this technology only offers these benefits to liquid phase reactions. With Peptides we know Solid phase synthesis is still the only viable method for amino acid couplings, but with post cleavage steps like cyclisations, continuous flow technology can still play a significant role in the synthesis of peptides. At Ipsen we have investigated how continuous flow can change the way we manufacture.
In this case study the CMC development, scale-up and large scale manufacturing of Octreotide Acetate will be described. The talk will also consider the control strategy (starting material quality, in-process controls, API specifications). Process robustness is demonstrated comparing process parameters and drug substance quality attributes from process development and scale-up batches.
The presentation includes the performance of Molecular HivingTM Technology, tag-assisted liquid phase peptide synthesis, for manufacturing peptide focusing on low cost, high quality and short lead time.
Mutations in NOD2 protein are associated with multiple immune disorders. We have developed a solid phase approach that reduces the number of steps and purifications required in traditional solution phase synthesis and generated NOD2 ligand MDP with several functional groups (biotin, alexa, flag). These modified MDP based probes will allow the biological evaluation of the interaction of MDP and NOD2.
Regulatory specifications are a key requirement for any product registration that must be agreed between the peptide CMO and the sponsor as well as carefully justified to regulatory authorities. Within the PolyPeptide Group, the API registered specifications are not only based on process capabilities but also developed from a thorough process understanding and a comprehensive process and peptide characterization that goes beyond routine testing methods. API specifications are tightened and fine-tuned as clinical phases progress and manufacturing process matures. The approach followed and methodologies used will be further described and exemplified.
Chemo-enzymatic peptide synthesis (CEPS) has been proven to be a cost effective and scalable technology for the large scale manufacture of peptide therapeutics. In this lecture, several case studies of CEPS applied to the manufacture of linear (e.g thymosin-a1, exenatide and other GLP-1 analogues) and (multi-)cyclic peptides (e.g. cyclotides such as MCoTI-II or Kalata B1) will be discussed.
After process improvements in the cleavage step an impurity was formed at a higher level in the crude product which led to a GMP-batch of a branched peptide with an impurity at a level >1,0%. The presentation will summarize the structure elucidation, the formation and the cure of this issue.
Continuous countercurrent chromatography is a valuable tool for the purification of peptides produced by chemical synthesis. Using a process comprising two reverse-phase columns and internal recycling (MCSGP), peptides are purified on a preparative scale with high yield and purity simultaneously while the generation of side-fractions and re-chromatography is avoided. The talk introduces the process concept and recent results of preparative peptide purification by countercurrent chromatography, such as a UV-based dynamic process control concept and an economic analysis.
Native chemical ligation (NCL) is arguably the most powerful method for protein chemical synthesis. However, the requirement of cysteine at the ligation junction and the need for repeated HPLC purification limit the throughput of synthesis endeavors. I will report capture-release/solid-supported strategies and a new auxiliary category which omit the need for HPLC and broaden the scope of NCL chemistry.