In 2014, Amgen opened a US$200 million (€168 million) next-generation production facility in Singapore intended to manufacture biologics with greater speed, productivity and flexibility. The model is being replicated at another facility under construction at Amgen’s West Greenwich, Rhode Island, campus.
The two manufacturing plants are based on enabling technologies including single-use, modular design, and process intensification.
Smaller Manufacturing but Larger Media Footprint
These reduce the facility’s footprint compared to a conventional manufacturing plant, Sara Gall, principal engineer at Amgen USA told delegates in Amsterdam in April.
“All of these things have really for us brought a tremendous shift as to how we manufacture our molecules, but it’s also brought some additional challenges,” she said at the BPI European Summit.
As Amgen has gone from fed-batch bioreactors to perfusion-based systems, the amount of media required has increased, she continued.
“For us we’re actually using more media with smaller bioreactors than we did when we had fed-batch bioreactors, so we’re shifting that burden of manufacturing from the bioreactors themselves into being media compounding facilities.”
Using tens of thousands of liters of media presents challenges with storage, especially when trying to reduce the footprint of a facility, as well as with dissolution and preparation time when used in small single-use vessels.
“In Singapore, we employ the use of 5,000 L single-use mixers,” Gall said. “These are very large single-use mixers and they don’t have the mixing dynamics, so what happens is it can take a really long time when you add that media powder to the top of that vessel for it to sink into the liquid.”
This can be as long as four hours just waiting for the media powder to dissolve in the water, “and that puts stress on our manufacturing colleagues in terms of trying to make media before bioburden begins to proliferate.”
Compounding and Concentration
Amgen, therefore, has undertaken a development program to make a “more manufacturing friendly” media for some of its molecules in development.
The firm has looked into compounding its media in the stainless steel mixers faster through technologies to address the dissolution issues. “One of these is media powder compaction” Gall said, enabled through a fine powder media offered by MilliporeSigma.
Compacted powder with larger granules seems counter intuitive as they would potentially take longer to dissolve, but this media avoids the issue of powder sitting at the top of the mixer and not sinking in.
“They’ve worked to develop what is the optimal diameter of media powders so that it does sink but you still get faster solution,” Gall said.
She added Amgen has coupled this compacted media with a five-times increase in concentration, and found after numerous studies – from bench scale to 2,000 L commercial scale – that there is no product quality impact.
Reduced Single-Use, Reduced Costs
Media granulation and concentrates will improve media compounding speed and manufacturability with minimal process or product impact, she said, and furthermore when this is translated into costs could save Amgen as much as US$30,000 per run.
“Every single media prep you make you have the prefiltration single-use bag, as well as the bag that you store it in, and for us we’re able to significantly reduce that.”