Development of a Control Strategy for Benzene Impurity in HPMCAS-Stabilized Spray-Dried Dispersion Drug Products Using a Science-Based and Risk-Based Approach.
OBJECTIVE
To develop a strategy to control benzene, an ICH Q3C Class 1 impurity that may be present in spray solvents at ppm concentration, in amorphous polymer-stabilized spray-dried dispersion (SDD) products.


METHODS
Risk assessments included determining the probability for benzene concentration in primary spray solvents, the physical properties of volatiles, and the potential enrichment of benzene from solution to solid. Mechanistic understanding of benzene removal was gained through a benzene-spiked fate and tolerance (F&T) study simulating worst-case spray-drying conditions and application of diffusion models for secondary drying.


RESULTS
The mass ratio of spray solution to solid presented the highest risk of benzene enrichment. With slow spray-drying kinetics, benzene was reduced about 700-fold. Under standard secondary-drying conditions to remove residual solvents, residual benzene was further removed. Using diffusion models, the maximum benzene concentration was approximated for SDDs dried to the in-process control (IPC) limit of primary solvents.


CONCLUSIONS
Two critical control points were established to eliminate any risk of residual benzene reaching patients: (1) upstream control of benzene in solvents (≤10 ppm) and (2) IPC of residual solvents in polymer-stabilized SDDs.
Analytical and Bioanalytical Development, Bristol-Myers Squibb Company, One Squibb Drive, New Brunswick, New Jersey, 08903, USA, hongfei.yue@gmail.com.
Hongfei
H
Yue
Sarah J
SJ
Nicholson
Joel D
JD
Young
Daniel
D
Hsieh
Rodney J
RJ
Ketner
Robert G
RG
Hall
Jeremy
J
Sackett
Elizabeth C
EC
Banks
John A
JA
Castoro
Michael E
ME
Randazzo
D000096:Acetone; D001554:Benzene / Q000032:analysis*; D002849:Chromatography, Gas; D003890:Desiccation; D004058:Diffusion; D004339:Drug Compounding; D004340:Drug Contamination / Q000517:prevention & control*; D005079:Excipients / Q000737:chemistry*; D000432:Methanol; D008747:Methylcellulose / Q000031:analogs & derivatives* / Q000737:chemistry; D015233:Models, Statistical; D015203:Reproducibility of Results; D018570:Risk Assessment; D012997:Solvents
D005079:Excipients; D012997:Solvents; D000096:Acetone; C048331:hydroxypropylmethylcellulose acetate succinate; D008747:Methylcellulose; D001554:Benzene; D000432:Methanol