There have been a number of investments recently in medium-sized bioreactors (2,000L single-use by Fujifilm, Rentschler etc) and at an event yesterday hosted by Repligen – manufacturer of growth factors, protein A and chromatography products – Howard Levine, President of Bioprocess Technology Consultants, explained why this type of investment was displacing traditional 10-20,000L stainless steel vessels.
Approximately a third of products on the biopharma market are monoclonal antibodys (mAbs), he told investors with sales of $49bn (€38bn) in 2013. MAbs and their alternative more potent formats –bispecific antibodies and antibody-drug conjugates, for example - account for over 75% of the 600 bio-products in development in the US and Europe, and thus “the biopharmaceutical industry is becoming to a large extent a monoclonal antibody industry,” he said.
This, coupled with a shift away from blockbusters to smaller niche markets, personalised medicines and orphan drugs, is changing the manufacturing process, he told stakeholders.
“In 2013, requirements for each of the top five mAbs ranged from 1 – 5 metric tonnes. By comparison, all others combined – approximately 45 products - required approximately 4 metric tonnes. Most of the pipeline products will require less than 100kg per year and can be produced in bioreactors much smaller than we see today.”
Of the 318 biopharmaceuticals in Phase II and III clinical trials, over 75% of manufacturing needs can be met in bioreactors of 5,000L or smaller, he argued, adding the shift away from the large traditional stainless steel bioreactors was also being encouraged by advances in process efficiencies which have increased titres 5-7 fold.
“In the late 80s and early 90s, expression levels were 1g per litre or less, with an overall yield of 50-60%. This means 100kg of products required 17 runs which is essentially full capacity in a plant using a 10,000L bioreactor. Today a state of the art facility runs at expression levels of 5g per litre with a 70% overall yield, and 100kg requires 15 runs at 2,000L.”
The added pressure of markets such as China which requires local manufacturing, or Brazil which offers incentive for home-grown products, is also encouraging the smaller, more flexible facility model he said. Furthermore, capital investment and operating costs are lower than traditional stainless steel facilities by up to 25% he argued.
He admitted stainless steel and large volume still has its uses and 20,000L vessels play their part in economies of scale – Pfizer has spoken of the burden of single-use in its commercial manufacturing sites – but added even in these traditional facilities manufacturers are requiring more flexibility.
“There are a lot of companiess like Genetech which have large installed stainless steel bioreactors. They are not going to simply throw these away, instead as their processes get more efficient, those facilities will become multi-product facilities making 2-3, rather than just one product.”