Lecture 12 - Slides Pharmaceutical Industry.pdf

Applications of separation science in the pharmaceutical industry (with a focus on stability indicating method development) Paul Ferguson Outline Medicines and analytical chemistry Method development for stability indicating...

Applications of separation science in the pharmaceutical industry (with a focus on stability indicating method development) Paul Ferguson Outline Medicines and analytical chemistry Method development for stability indicating methods Timelines for development of a medicine Fundamental physico-chemical Nomenclature of documents associated with understanding medicine submission Sample preparation considerations Types of methods developed at each stage of In-silico tools the development pipeline Method robustness Compliance levels and implications Method validation Regulatory bodies Method transfer Regulatory guidance Recap Specifications Control strategy Common Technical Document Development of medicines Development of a medicine is a complex multidisciplinary process Involves many different types of scientists Very high attrition rate Development can take 10-15 years Limited time to recoup development costs and invest in new therapies Key drugs can be accelerated with regulatory body support Highly regulated https://www.ece.rutgers.edu/news/software-framework-designed-accelerate-drug-discovery What do pharmaceutical analytical chemists do? Develop and validate analytical methods for the testing of raw materials, intermediates, active ingredient and drug product Clinical release and stability testing to allow material to be used in use in clinical trials and develop an understanding of shelf life Develop detailed understanding of impurities in the manufacturing processes and degradation products to ensure quality is met and supply managed Deliver regulatory documentation to show health authorities our depth of understanding and control of quality Collaborate with other analysts, chemists, engineers, crystallisation experts, pharmacists and project managers…… Strong emphasis on the development of a control strategy to ensure medicine quality and patient safety What analytical techniques are used? HPLC/UHPLC Gas Chromatography (GC) Mass spectrometry (MS) API and drug product Assay of small volatile Structural elucidation quantitative assay compounds e.g. Trace level quantification e.g. Related substances Raw materials PMIs, nitrosamines Degradation products Potentially mutagenic Dissolution ‘finish’ impurities (PMI’s) Uniformity of content (UoC) Residual solvents What analytical techniques are used? Ion chromatography (IC) Size exclusion Capillary Electrophoresis Residual metals chromatography (SEC) Chiral analysis Small organic counter-ions MW distribution of polymer pKa determination Certain chemical classes e.g. excipients Numerous biomolecule carbohydrates, antibiotics Biomolecule characteristics measurements e.g. pI, aggregates What analytical techniques are used? Plus many more non-separative characterisation techniques Supercritical fluid Preparative chromatography chromatography (SFC) SFC or LC Chiral analysis Isolation of analytes for Reaction monitoring characterisation Water labile analytes Pharmaceutical development timeline Discovery analytical Early development Full Development High throughput High efficiency fast Bespoke method development rapid assay/purity generic methods Stability indicating method for generic methods Some bespoke pivotal stability studies method Focus on robustness and development transferability Separation science method requirements Robustness Speed New route or in-licensed project Peak Capacity On-market CSID Ph 1 Ph 2a Ph 2b Ph 3 support Development timeline (not to scale)  Separation science in drug discovery (pre-clinical) Rapid reaction monitoring Fast throughput, open access UPLC-MS for monitoring target products, starting materials and side reaction products during medicinal chemistry reactions Chromatographic method development prior to sample purification Rapid gradient UPLC-MS and SFC-MS analysis to assess chromatographic profile and RT of target species prior to achiral purification Mass-triggered purification platforms – SFC-MS and HPLC-MS to isolated target species from crude reaction mixtures Final compound QC Open access UPLC-MS to identify and assess purity of final compounds prior to compound registration 10  Separation science in drug discovery (pre-clinical) Pre in-vivo purity assessment Targeted and orthogonal UPLC-MS analysis to assess samples purity prior to in-vivo experiments Chiral method development and preparative isolation of enantiomers Orthogonal SFC and HPLC analytical screens to develop chromatographic methods for chiral separation of enantiomers SFC and HPLC separation and isolation of enantiomeric species from racemic mixtures 11 Separation science in drug discovery (pre-clinical) UPLC/MS method SFC/MS method Mobile Phase A: 0.05% formic acid or 0.1% Mobile Phase A: CO2 ammonium hydroxide in water Mobile Phase B: MeOH + 0.1% ammonium Mobile Phase B: acetonitrile hydroxide Column: C18, 50 x 2.1 mm i.d.,