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Manufacture Bioprocessing - Upstream & Downstream

Exploring the Product–Process Relationship

The term ‘biopharmaceutical’ was first introduced in the 1980s, and the market has been growing ever since – and it seems safe to assume that biopharmaceutical development will remain a focal point for the pharma industry. And that’s a good thing – because it’s a fascinating area to research from where I’m standing.

We all know that there are significant distinctions between biopharmaceuticals and traditional small-molecule drugs due to fundamental differences in their syntheses and structures. The complexity of biopharmaceutical molecules poses numerous manufacturing challenges that are not seen with conventional chemical small molecules. And I am not just talking about the physical manufacturing steps, but the entire relationship between product and process innovation.

In a recent study, Minsuk Suh, Professor at Hanyang University in Korea, and I examined how biopharmaceutical R&D processes – and the product–process relationship – have evolved to become so distinct from small-molecule drugs. We did this by tracking, categorizing, and comparing patented pharmaceutical and biopharmaceutical technologies in development cycles (1).

Our findings are important because an understanding of the product–process relationship can lead to more efficient lifecycle management. I also think our work is interesting for simple curiosity’s sake – for example, by answering questions, such as at what stage of drug development do you see the highest number of patent registrations? For small molecules, it’s right at the last moment – just before the regulatory approval stage. For biopharmaceuticals, patent registrations are more spread out.

To understand the patterns of innovations, we began with Abernathy and Utterback’s product lifecycle model of innovation, which addresses changes in patterns of product and process innovations at each development stage (2). Utterback showed that the rate of product innovation exceeds the rate of process innovation at the initial stage. Basically, this means that firms invest in new processes only after products are developed. You generally see this in the development of small-molecule drugs.

But isn’t science – and the pharma industry – supposed to be a process-enabling industry where fast, efficient, and high-quality process development has a direct impact on finished product development? This is a familiar concept in the pharma industry thanks to the implementation of Quality by Design (QbD) (3). The key outcome of the QbD conceptual framework is that quality should be built into a product via a thorough understanding of both the product and process. The quality of a biopharmaceutical is comprehensively determined by both process and process conditions, which should be carefully managed throughout the entire development and manufacturing procedures. In other words, process innovation cannot be separated from the biopharma product’s lifecycle.

And indeed, the results of our study show that patents related to biopharmaceutical products show stronger relationships with process innovations than those related to traditional chemical pharmaceuticals. Chemical pharmaceuticals show an asymmetric pattern in innovations, where there is a significant portion of R&D conducted just prior to the commercial launch phase. For example, there is a tendency not to focus on the process too much until promising outcomes can be expected from Phase III trials. Such a strategy has emerged because process development for the production of chemical drugs is generally well defined and focused primarily on production scaling to meet commercial volume requirements.

The findings of our study are valuable when it comes to decision making in biopharmaceutical drug development.

For biopharmaceuticals, our study showed that product and process innovation activities are more evenly distributed throughout development. This is because biopharmaceutical product and process development activities are inseparable throughout the R&D cycle. Both the product and process innovations for biopharmaceuticals are initiated very early – right at the discovery stage – to establish a fundamental technological basis applicable to commercial production scales.

In my view, the findings of our study are valuable when it comes to decision making in biopharmaceutical drug development. For biopharmaceuticals, you must be prepared to make decisions about in-house manufacturing and investment in human resources much earlier in the development cycle compared with small-molecule drugs. You may also have to revisit decisions after a product is approved for the market, since commercial-scale production must be explored both before and after approval. Moreover, the integrated nature of biopharmaceutical innovations should be reflected differently in knowledge management strategies and capital allocations.

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  1. S.Y. Lim and M. Suh, “Product and Process Innovation in the Development Cycle of Biopharmaceuticals, ”  J. Pharm. Innov. (2015). doi: 10.1007/s12247-015-9214-9
  2. J. Utterback, Mastering the dynamics of innovation, published by Harvard Business School Press (1196). ICH Q10 Pharmaceutical Quality System (2008).
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