In recent years, regulatory agencies have zeroed in on the presence of heavy metals in pharmaceutical and biopharmaceutical drug substances.

The previous analytical method standard for heavy metals characterization - described in USP 231 – has been eliminated in favor of inductively coupled plasma (ICP) techniques such as ICP atomic emission spectroscopy, ICP optical emission spectroscopy and – in particular – ICP mass spectrometry (ICP-MS), which has detection limits as low as 1 part per billion (ppb).

The result has been more stringent regulation of allowable metal content in APIs.
The list of metals to be assessed has been expanded by regulators, and now includes arsenic, cadmium, lead and mercury in all samples, plus chromium, copper, iridium, molybdenum, nickel, osmium, palladium, platinum, rhodium, ruthenium and vanadium where appropriate.

ICH Q3D GUIDELINE FOR ELEMENTAL IMPURITIES

In the past 20 years, the use catalysts in the synthesis of drug molecules have been prevalent. They allow the introduction of functionalities and / or of chirality that stochiometric reagents are not able to accomplish as efficiently. Furthermore, they offer several advantages as they are scalable from lab to commercialization scale, and they address complex synthetic chemical structures. However, most of the metals used in catalysis can be toxic at a certain dose and therefore need to be removed from the final product.

Companies must therefore balance controlling costs, pressure to develop drugs in shorter time frames, vigilance of metals and stronger regulatory controls.

What Happens When a Pharma Company Has a Palladium (Pd) Challenge?

We worked with a mid-sized pharma company on an API R&D project (Two-Steps Purification with E-PAK® Cartridges Following a Direct Pd-Catalyzed Borylation). During the project, we evaluated replacing an existing – and complex – 5-step filtration process to reduce palladium (Pd) levels to lower than 20 ppm.

The original Pd removal process included:

  • 1st filtration on activated carbon followed by washings
  • 2nd washing of the obtained organic phase with conc. HCl to achieve an effective phase separation
  • 2nd filtration on activated carbon followed by washings
  • Treatment with SiliaMetS Thiol for 6 hours
  • 3rd filtration, followed by evaporation
  • Recrystallisation

By the end of the study, we successfully replaced multiple, complex steps with E-PAK carbon cartridges operating at room temperature. (Read the full case study here).

E-PAK Systematizes and Scales Your Metal Scavenging

E-PAK filters help pharma companies systematize and industrialize the process of removing unwanted metals from drug intermediates and APIs. They can be used at different steps during the synthesis of the molecule. If possible, we suggest their use right after the catalytic reaction but if this not possible, they can be used further down the process as the last step.

Based on our SiliaMetS product line and commonly used activated carbons, SiliCycle developed E-PAK technology for the removal of metal impurities in solution down to suitable ppm levels. The E-PAK cartridges offer several advantages:

  • Process steps can be combined
  • Filtration steps can be eliminated
  • They are used as fixed bed or flow purification
  • They allow for different configurations for purification optimization
  • Several cartridges can be used in series or within the same housing
  • They use radial flow, allowing their use at low pressure

E-PAK, with its small footprint housing, was also specifically designed for convenient placement of the purification apparatus next to reaction vessels.

Straightforward Scalability

As everyone in R&D knows, pharmaceutical process scalability can be challenging. Processes rarely scale-up in a linear fashion. Challenges and concerns at bulk scale seldom mirror those from the lab bench.

When it comes to metal scavenging, however, E-PAK removes the scale-up uncertainties alongside the metal contaminants. E-PAK scale-up is straightforward – from the lab bench to pilot scales, through to bulk commercial runs of several hundred kilograms – and has excellent linearity.

Once the various scavenging yield parameters have been defined, it is a simple matter to operate E-PAK cartridges in parallel to increase capacity.

Multi-cartridge housings can be used to take advantage of the different affinity of the E-PAK activated carbon and SiliaMetS to get to the desired scavenging yield. We currently provide the 3, 7 and 12 rounds housing for scaling up to hundreds of kilos.

Metal scavenging has become a routine practice in drug manufacturing, but it can also require innovative purification strategies. A turnkey solution like E-PAK technology is scalable and flexible enough to handle complex removal challenges – easing process development and commercial manufacturing operations while controlling costs.

Learn more about E-PAK® cartridges

Learn more about SiliaMetS® Metal Scavengers

For further information

Ready get started with E-PAK, or want to learn more?
Contact us: scavengers@silicycle.com.