title: A PAT-based qualification of pharmaceutical excipients produced by batch or continuous processing.
abstract: Pharmaceutical excipients have an influence on the main requirements for medicinal products (viz., quality, safety and efficacy) but also on their manufacturability. During product lifecycle it may become necessary to introduce minor changes (e.g., to continuously improve it) or major changes in the validated process (e.g., moving it to a new production site, replacing process version or even disruptively changing processing type). Those changes can influence the critical to quality attributes of the product. Therefore, it is important to enhance process understanding to avoid the risk of any significant quality changes. Process analytical technology can support better decision making and risk-management as required in quality by design - viz., by many pharmaceutical regulatory authorities. This study compares the quality of the pharmaceutical excipient sodium carbonate (anhydrous) produced either in a batch or a continuous process. For continuous processing two different production lines were available that differed on the dryer and crystallizer types used. Therefore their influence on critical to quality attributes of sodium carbonate was investigated for each of the three processing alternatives. The overall goal was to identify which of the continuous processes ensures a similar product quality to batch processing. Namely, changes on chemical and physical attributes of the product were investigated with Raman spectroscopy, laser diffraction and X-ray powder diffraction. Principal component analysis, a very common multivariate analysis technique, was applied to extract relevant information from small differences at multiple spectral regions from samples from each process type and from each analytical technique used. Changing processing from batch to continuous improved consistency of certain attributes (e.g., particle size distribution) but affected others. However, the increased process/product knowledge gained can lead to an enhanced control strategy and ensure a similar product quality is obtained from distinct process versions.
authors.affiliation: Quality Operations, Laboratory for Liquid Products, Merck Serono, Frankfurter Str. 250, 64293 Darmstadt, Germany; Institute for Biotechnology and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal. Electronic address: alexandra.hertrampf@external.merckgroup.com.
authors.forename: A
authors.initials: A
authors.lastname: Hertrampf
authors.affiliation: Operations, Laboratory for Process Development, Merck Millipore, Frankfurter Str. 250, 64293 Darmstadt, Germany. Electronic address: heike.m.mueller@merckgroup.com.
authors.forename: H
authors.initials: H
authors.lastname: Müller
authors.affiliation: Institute for Biotechnology and Biosciences, Instituto Superior Técnico, Universidade de Lisboa, Av. Rovisco Pais, 1049-001 Lisbon, Portugal. Electronic address: cardoso.menezes@tecnico.ulisboa.pt.
authors.forename: J C
authors.initials: JC
authors.lastname: Menezes
authors.affiliation: Quality Operations, Laboratory for Liquid Products, Merck Serono, Frankfurter Str. 250, 64293 Darmstadt, Germany. Electronic address: thorsten.herdling@merckgroup.com.
authors.forename: T
authors.initials: T
authors.lastname: Herdling
mesh_terms: D002626:Chemistry, Pharmaceutical / Q000379:methods*; D016002:Discriminant Analysis; D005079:Excipients / Q000737:chemistry*; D007834:Lasers; D016014:Linear Models; D008855:Microscopy, Electron, Scanning; D015999:Multivariate Analysis; D010316:Particle Size; D004364:Pharmaceutical Preparations / Q000032:analysis*; D011208:Powders; D011786:Quality Control; D013059:Spectrum Analysis, Raman; D013678:Technology, Pharmaceutical / Q000379:methods; D014961:X-Ray Diffraction
chemical_list: D005079:Excipients; D004364:Pharmaceutical Preparations; D011208:Powders
keywords: Multivariate data analysis; Pharmaceutical engineering; Pharmaceutical excipients; Process analytical technology; Quality control strategy; Supplier qualification