title: Application of In-line Focused Beam Reflectance Measurement to Brivanib Alaninate Wet Granulation Process to Enable Scale-up and Attribute-based Monitoring and Control Strategies.
abstract: Application of in-line real-time process monitoring using a process analytical technology for granule size distribution can enable quality-by-design development of a drug product and enable attribute-based monitoring and control strategies. In this study, an in-line laser focused beam reflectance measurement (FBRM) C35 probe was used to investigate the effect of formulation and process parameters on the granule growth profile over time during the high shear wet granulation of a high drug load formulation of brivanib alaninate. The probe quantitatively captured changes in the granule chord length distribution (CLD) with the progress of granulation and delineated the impact of water concentration used during granulation. The results correlated well with offline particle size distribution measured by nested sieve analyses. An end point indication algorithm was developed that was able to successfully track the process time needed to reach the target CLD. Testing of the brivanib alaninate granulation through 25-fold scale-up of the batch process indicated that the FBRM CLD profile can provide a scale-independent granule attribute-based process fingerprint. These studies highlight the ability of FBRM to quantitate a granule attribute of interest during wet granulation that can be used as an attribute-based scale-up and process monitoring and control parameter.
authors: Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903. Electronic address: Ajit.Narang@BMS.com.
authors: Ajit S
authors: AS
authors: Narang
authors: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors: Timothy
authors: T
authors: Stevens
authors: Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors: Kevin
authors: K
authors: Macias
authors: Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors: Srinivasa
authors: S
authors: Paruchuri
authors: Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors: Zhihui
authors: Z
authors: Gao
authors: Drug Product Science & Technology, Bristol-Myers Squibb Company, One Squibb Dr., New Brunswick, New Jersey 08903.
authors: Sherif
authors: S
authors: Badawy
mesh_terms: D000409:Alanine / Q000031:analogs & derivatives* / Q000737:chemistry; D004339:Drug Compounding / Q000379:methods*; D005079:Excipients / Q000737:chemistry; D007834:Lasers; D010316:Particle Size; D011208:Powders; D014227:Triazines / Q000737:chemistry*; D014867:Water / Q000737:chemistry
chemical_list: D005079:Excipients; D011208:Powders; D014227:Triazines; D014867:Water; C509922:brivanib; D000409:Alanine
keywords: FBRM; focused beam reflectance measurement; formulation; granulation; high shear wet granulation; high throughput technologies; powder technology; process analytical technologies; processing; unit operations