Roche on excipient inconsistencies: ‘Don’t blame suppliers, work with them’

Poloxamer 188 (P188) is a non-ionic triblock copolymer excipient used to enhance the solubility of small molecule drugs. It is also used in culture media to prevent shear forces damaging cell surface proteins and to reduce cell-bubble attachment.

Having consistent reagents is vital according to Salim Charaniya from Roche subsidiary Genentech, whose case study at the Bioprocessing International Europe (BPI) summit last week showed how P188 variability had reduced titre 40% and product 30% in a previous manufacturing operation.

“This [reduction] was reproduced in multiple batches and we actually saw many different batches getting impacted. Combined together, the total cost of that impact was several millions of dollars for Roche.”​

But when Genentech switched the Poloxomer lot the process returned back to normal, he told a crowded room in Amsterdam, giving the firm “a good indication that variability in Poloxomer lots can have an impact on this critical process.”​

BASF collaboration​

For this particular and undisclosed biologic – made using the CHO cell line and in multiple facilities – the excipient was supplied by German chemical company BASF.

“When we actually changed the Poloxomer lot for a different vendor lot, we saw right away the process going back to normal,”​ Charaniya said. “As soon as we switched the lot there was no impact [on production] so that was a clear indication.”​

But rather than blame BASF, Roche/Genentech worked with the vendor to understand what had caused the variability. Results found traces of hydrophobic surface active compounds present in the high molecular weight of the excipient, even at very low levels, can impact performance.

“As an outcome of this investigation there were measures and controls implemented by BASF to eliminate those hydrophobic traces which will hopefully be providing us with consistent lots of Poloxomer for cell culture going forward.”​

Since the collaboration, Roche has received validation for an assay developed to screen every lot of P188 before using it for GMP manufacturing, and continues to use BASF as a P188 supplier, Charaniya continued.

He added it was “fascinating”​ how such small quantities of hydrophobic traces had such an impact on performance, and while the reason is still unknown vendor collaboration was – and remains key – in investigating such unidentified issues in biomanufacturing.

“Don’t blame the supplier, work with them to advance knowledge, and that is what we have tried to do in this example.”​

Roche and BASF are not alone in finding discrepancies across batches of the shear protectant excipient. Both drugmaker Biogen​ and supplier SAFC​ (now part of Merck Millipore) have released separate papers on the lot-to-lot issues with Poloxamer 188.