PMID- 23764657
OWN - NLM
STAT- MEDLINE
DCOM- 20140324
LR  - 20130626
IS  - 1873-264X (Electronic)
IS  - 0731-7085 (Linking)
VI  - 83
DP  - 2013 Sep
TI  - On-line near infrared spectroscopy as a Process Analytical Technology (PAT) tool 
      to control an industrial seeded API crystallization.
PG  - 194-201
LID - S0731-7085(13)00216-1 [pii]
LID - 10.1016/j.jpba.2013.05.015 [doi]
AB  - The final step of an active pharmaceutical ingredient (API) manufacturing 
      synthesis process consists of a crystallization during which the API and residual 
      solvent contents have to be quantified precisely in order to reach a predefined 
      seeding point. A feasibility study was conducted to demonstrate the suitability 
      of on-line NIR spectroscopy to control this step in line with new version of the 
      European Medicines Agency (EMA) guideline [1]. A quantitative method was 
      developed at laboratory scale using statistical design of experiments (DOE) and 
      multivariate data analysis such as principal component analysis (PCA) and partial 
      least squares (PLS) regression. NIR models were built to quantify the API in the 
      range of 9-12% (w/w) and to quantify the residual methanol in the range of 0-3% 
      (w/w). To improve the predictive ability of the models, the development procedure 
      encompassed: outliers elimination, optimum model rank definition, spectral range 
      and spectral pre-treatment selection. Conventional criteria such as, number of 
      PLS factors, R(2), root mean square errors of calibration, cross-validation and 
      prediction (RMSEC, RMSECV, RMSEP) enabled the selection of three model 
      candidates. These models were tested in the industrial pilot plant during three 
      technical campaigns. Results of the most suitable models were evaluated against 
      to the chromatographic reference methods. Maximum relative bias of 2.88% was 
      obtained about API target content. Absolute bias of 0.01 and 0.02% (w/w) 
      respectively were achieved at methanol content levels of 0.10 and 0.13% (w/w). 
      The repeatability was assessed as sufficient for the on-line monitoring of the 2 
      analytes. The present feasibility study confirmed the possibility to use on-line 
      NIR spectroscopy as a PAT tool to monitor in real-time both the API and the 
      residual methanol contents, in order to control the seeding of an API 
      crystallization at industrial scale. Furthermore, the successful scale-up of the 
      method proved its capability to be implemented in the manufacturing plant with 
      the launch of the new API process.
CI  - Copyright (c) 2013 Elsevier B.V. All rights reserved.
FAU - Schaefer, C
AU  - Schaefer C
AD  - UCB Pharma, Analytical Development Chemicals, Chemin du Foriest, 1420 
      Braine-l'Alleud, Belgium. cedric.schaefer@ucb.com
FAU - Lecomte, C
AU  - Lecomte C
FAU - Clicq, D
AU  - Clicq D
FAU - Merschaert, A
AU  - Merschaert A
FAU - Norrant, E
AU  - Norrant E
FAU - Fotiadu, F
AU  - Fotiadu F
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130520
PL  - England
TA  - J Pharm Biomed Anal
JT  - Journal of pharmaceutical and biomedical analysis
JID - 8309336
RN  - 0 (Pharmaceutical Preparations)
SB  - IM
MH  - Crystallization/*methods
MH  - Drug Industry/*methods
MH  - Least-Squares Analysis
MH  - Models, Theoretical
MH  - Multivariate Analysis
MH  - Pharmaceutical Preparations/*chemistry
MH  - Principal Component Analysis/methods
MH  - Spectroscopy, Near-Infrared/*methods
EDAT- 2013/06/15 06:00
MHDA- 2014/03/25 06:00
CRDT- 2013/06/15 06:00
PHST- 2013/02/18 00:00 [received]
PHST- 2013/05/07 00:00 [revised]
PHST- 2013/05/13 00:00 [accepted]
PHST- 2013/06/15 06:00 [entrez]
PHST- 2013/06/15 06:00 [pubmed]
PHST- 2014/03/25 06:00 [medline]
AID - S0731-7085(13)00216-1 [pii]
AID - 10.1016/j.jpba.2013.05.015 [doi]
PST - ppublish
SO  - J Pharm Biomed Anal. 2013 Sep;83:194-201. doi: 10.1016/j.jpba.2013.05.015. Epub 
      2013 May 20.