A Process Analytical Technology (PAT) approach to control a new API manufacturing process: development, validation and implementation.
Pharmaceutical companies are progressively adopting and introducing Process Analytical Technology (PAT) and Quality-by-Design (QbD) concepts promoted by the regulatory agencies, aiming the building of the quality directly into the product by combining thorough scientific understanding and quality risk management. An analytical method based on near infrared (NIR) spectroscopy was developed as a PAT tool to control on-line an API (active pharmaceutical ingredient) manufacturing crystallization step during which the API and residual solvent contents need to be precisely determined to reach the predefined seeding point. An original methodology based on the QbD principles was designed to conduct the development and validation of the NIR method and to ensure that it is fitted for its intended use. On this basis, Partial least squares (PLS) models were developed and optimized using chemometrics methods. The method was fully validated according to the ICH Q2(R1) guideline and using the accuracy profile approach. The dosing ranges were evaluated to 9.0-12.0% w/w for the API and 0.18-1.50% w/w for the residual methanol. As by nature the variability of the sampling method and the reference method are included in the variability obtained for the NIR method during the validation phase, a real-time process monitoring exercise was performed to prove its fit for purpose. The implementation of this in-process control (IPC) method on the industrial plant from the launch of the new API synthesis process will enable automatic control of the final crystallization step in order to ensure a predefined quality level of the API. In addition, several valuable benefits are expected including reduction of the process time, suppression of a rather difficult sampling and tedious off-line analyses.
UCB Pharma, Analytical Development Chemicals, Avenue de l'Industrie, 1420 Braine-l'Alleud, Belgium; Institut des Sciences Moléculaires de Marseille, CNRS, UMR 7313, École Centrale Marseille, Aix Marseille Université, Avenue Escadrille Normandie-Niemen, Case A62, 13397 Marseille cedex 20, France. Electronic address: cedric.schaefer@ucb.com.
Cédric
C
Schaefer
UCB Pharma, Analytical Development Chemicals, Avenue de l'Industrie, 1420 Braine-l'Alleud, Belgium.
David
D
Clicq
UCB Pharma, Chemical Process Development, Avenue de l'Industrie, 1420 Braine-l'Alleud, Belgium.
Clémence
C
Lecomte
UCB Pharma, Chemical Process Development, Avenue de l'Industrie, 1420 Braine-l'Alleud, Belgium.
Alain
A
Merschaert
UCB Pharma, Innovation & Technology Development, Avenue de l'Industrie, 1420 Braine-l'Alleud, Belgium.
Edith
E
Norrant
Institut des Sciences Moléculaires de Marseille, CNRS, UMR 7313, École Centrale Marseille, Aix Marseille Université, Avenue Escadrille Normandie-Niemen, Case A62, 13397 Marseille cedex 20, France.
Frédéric
F
Fotiadu
D003460:Crystallization; D016018:Least-Squares Analysis; D004364:Pharmaceutical Preparations / Q000737:chemistry*; D019265:Spectroscopy, Near-Infrared / Q000379:methods*; D013678:Technology, Pharmaceutical / Q000379:methods*
D004364:Pharmaceutical Preparations
API crystallization; In-process control (IPC); Method validation; Near infrared spectroscopy; Process Analytical Technology (PAT); Quality-by-Design (QbD)