Expect the unexpected–screen your screens

✍ Scribed by Harish Ravivarapu; Sanjeev Redkar

• Publisher: John Wiley and Sons
• Year: 2011
• Tongue: English
• Weight: 35 KB
• Volume: 100
• Category: Article
• ISSN: 0022-3549
• DOI: 10.1002/jps.22424

✦ Synopsis

Rubitecan (9-nitrocamptothecin) has been investigated in multiple phase 3 clinical trials for the treatment of pancreatic cancer that supported a new drug application (NDA) with US Food and Drug Administration. The drug product is an oral, hard gelatine capsule in two strengths, 0.5 and 1.25 mg, respectively. Capsules constitute a homogenous, loosely bound, dry, pale-yellow powder blend of rubitecan, lactose monohydrate, colloidal silicon dioxide, and magnesium stearate. A number of NDA qualification and engineering batches were manufactured before embarking on validating the process and generating the initial commercial supplies. Unexpected difficulties were encountered during blend manufacturing that nearly failed the validation effort. Described below are lessons learned during the ensued investigation.

Rubitecan capsules are intended for oral administration and as the drug is poorly water soluble, drug particle size is reduced to impart better dissolution of drug and eventual higher drug uptake. Drug as is has a median diameter, D (v, 0.5) of 104 :m and an in-process specification of D (v, 0.5) 15-40 :m and D (v, 0.9) 50-125 :m was set based on manufacturing history of lots used in clinical studies. Because of this, micronization was not an option. Thus, a key step in the blend manufacturing was reduction of drug particle size by passing an initial blend of drug and lactose in 2:1 ratio through a rotating impeller, conical screen mill. Blend was sequentially screened twice through 152-:m screen and once through 228-:m screen.

During the manufacturing of the first validation batch, rapid and severe clogging of the 152-:m screen that was not seen before was observed with barely 20% of the fed blend passing through. This led to the abortion of the batch and initiation of a crossfunctional and extensive investigation to determine