Designing a winning process development strategy

Process development is an important aspect of biopharmaceutical development.^1,2 Through studies in the pharmaceutical industry, Pisano suggests that companies able to develop and implement new process technologies quickly and effectively have a competitive edge. In addition, the fact that the production cost of biopharmaceuticals could be up to 25% of sales value means that the failure to develop a viable process could result in uneconomic manufacturing routes and the inability to capture fully the value of the firm's discovery.³

A vice president for process R&D at Bristol-Myers Squibb, wrote: "At Bristol-Myers Squibb, process development is seen as a core competence and as an enabler of complex product design. Companies (and managers) that see process development and the development process as albatrosses run the risk of extinction, like the dodo".⁴

As the production process becomes locked in during development, process development activities that take place concurrently with clinical development determine the final production process, which is multi-dimensional and complex. Therefore, critical decisions have to be made during process development.^3,5

The uncertainty of clinical development and process development implies that biopharmaceutical development is highly complex and risky. The ability to plan for the uncertainty inherent in the development process is important for companies with finite resources for each development project.

Understanding process development

Process development activities are complex and linked to other issues within a firm. The complexity can be represented using a new conceptual, "development cycle".⁶ The development cycle involves formulating and agreeing objectives for the process design, taking into account the primary objective of the development, the product characteristics that result, the resources available and the clinical milestone to be met at the particular phase (Figure 1).

Figure 1 The development cycle.

Because the development cycle can be repeated throughout the development project, the concept takes into account the iterative nature of process development activities and other factors that are linked to them. Each cycle represents a certain process design, the resulting product characteristics, the resources required to support the development and the associated clinical requirements at that stage. This conceptual representation is consistent with the nature of the biopharmaceutical sector, which is characterized by unproven science and high uncertainty of market (Figure 2). Superior process development capability could play significant roles at firm level. For example

• accelerate time-to-market¹

• enable production ramp-up¹

• enhance customer acceptance of product¹

• provide competitive and strong proprietary position^1,7

• enhance product and process innovation^7,8

• enhance value capture⁷

These roles could provide leverage for companies to achieve their immediate business goals and long-term competitive advantage. However, the way that an individual firm gains leverage from the potential benefits of process development and production capability is dependent on the business model that the firm adopts.

Figure 2 Series of development cycles.

It may be that, for a certain type of business model (e.g., vertically integrated), process development is a crucial element, a complementary asset to its other operations; whereas for another type of business model (with a different value generation proposition), process development capability is less relevant and can be classified as a non-core capability. In such cases, it might be best if process development is outsourced or undertaken in partnership with organizations with the specialized knowledge and skills to tackle the problems.

What is best for your business?

Because process development requires an extensive amount of tacit knowledge and specialized assets, there is a large barrier to entry for bioprocessing.⁹ The option of undertaking in-house process development may not, therefore, be feasible for all companies, especially for small-and medium-size firms (SMEs) with limited capital (Table 1).

Table 1 Advantages and disadvantages of various process development approaches.

The inherent disadvantage in other options, other than undertaking process development in-house, is a loss of direct control. However, as noted by some industry experts, outsourcing is a way to address the problems of limitation of skills and resources in some smaller companies and, thus, is accepted as a standard practice of the drug development cycle.

As pointed out by a manufacturing director in a large biopharmaceutical company, "...this is because from an investment point of view, it is difficult to justify the large investment required for the set-up of an initial production facility for a product that might or might not be successfully developed."

The authors have found that different market sectors outsource for different reasons and view the outsourcing market as being composed of

• Virtual companies with funding, but that outsource the vast majority of their work. Typically, these companies may have the academic founder working part-time and a research assistant, and are housed within an academic laboratory.

• Small SMEs with less than 10 staff, typically working on early-stage development projects.

• Medium SMEs with 10–100 employees, typically with a number of products in the pipeline and possibly one or two in clinical trials.

The above groups fall into one of two sectors:

Competence limitations. The virtual companies and small SMEs are usually early-stage spin-outs from universities, medical schools and hospitals specializing in early pharmaceutical product discovery and research. These companies lack the skills to develop their research processes into manufacturing realities that meet with the requirements of the various international regulatory bodies — hence their need for the services of specialist companies.

As such, specialist contract process development companies are of value to these companies, initially to educate them into what is actually required and then using their process development experience to develop and deliver an appropriate process.

Resource limitations. Medium SMEs, because of their greater experience, understand the regulatory procedures and scale-up issues of the process development phase; however, they tend to be resource-limited either in terms of the facilities they have available or by the number of staff they can devote to any one project. In this case, the value of process development companies is in terms of offering extra capacity.

Golden rules

Although what is best for your business is context dependent, we propose eight golden rules in process development that we distill from experiences and insights gained from working with companies

• Keep in mind that at some stage the material will have to be made to GMP.

• However, also keep in mind the appropriateness of how much process development to perform early in the process.

• Consider how appropriate the expression system you are using is (e.g., mammalian, bacterial, etc).

• Consider the purification system (including use of his-tagged proteins).

• Have open discussions with CMOs early in the process to facilitate tech transfer.

• Be realistic on timescales.

• Be educated on what is needed prior to entering clinical trials.

• Give as much information as you have to your process development partner.

On top on the golden rules, it is also crucial that for projects undertaken in partnership with another party, clear goals are set to ensure that expectations from each of the partners are clearly laid out with corresponding timeframes and milestones. This will ensure effective communication and that both parties are on 'the same page'.

Conclusion

Because process development is a critical path activity in drug development, companies that are able to develop and implement new process technologies quickly and effectively have a competitive edge. However, process development is complex and expensive, and some companies may not have the in-house capabilities to tackle process development problems effectively. For these companies, there is the option of undertaking process development in partnership with a specialist service provider.

Jon Mowles is commercial director at CTM Biotech, Cambridge (UK). Lisa Lim is a doctoral researcher at the Institute for Manufacturing, University of Cambridge (UK).

References

1. G. Pisano, The Development Factory (Harvard Business School Press, Boston, MA, USA, 1997).

2. I. Cockburn et al., "Pharmaceuticals and Biotechnology," in D. Mowery, Ed., US Industry in 2000, Studies in Competitive Performance (The National Academy Press, Washington DC, USA, 2000).

3. S. Karri et al., Pharm. Technol. Eur. 13(9), 76–82 (2001).

4. C.M. Cimarusti, Harvard Business Review 73(6), 208 (1995).

5. N. Titchener-Hooker et al., Pharm. Technol. Eur. 13(9), 68–73 (2001).

6. L. Lim, E. Garnsey and M.J. Gregory, R&D Management 36(1), 27–36 (2006).

7. M.J. Gregory et al., Making the Most of Production (Institute of Manufacturing, Cambridge University, UK, 2003).

8. M. Feldman and C. Ronzio, Entrepreneurship & Regional Development 13(1), 1–16 (2001).

9. L. Lim, "Linking Process Development Capability to Business Models of Firms in the Biopharmaceutical Sector," Phd Thesis, Department of Engineering, University of Cambridge, UK (2005).