Continuing the theme of this occasional series, we examine the role of manufacturing in the supply chain in terms of what is required to deliver affordable medicines to patients. The industry has debated the relevance of manufacturing costs in the overall big picture (1). Rising manufacturing costs as a proportion of the overall selling price coupled with increased competitive pressures creates a strong drive to reduce manufacturing costs. However, cost of goods (CoG) is not the only strategic driver. Other important factors associated with bulk manufacturing are

• capital intensity (capital expenditure as a percentage of sales)

• timing of cash flows

• time taken to bring new capacity on board

• responsiveness to changes in demand

• flexibility, the ability to change over to a new product.

Inability to tackle some of those factors has caused significant problems for the biopharmaceutical industry during the past decade. A combination of capital intensity, uncertainty regarding product success, and long lead times required to build a large-scale facility has resulted in redundant capacity (2). Much capacity is no longer needed, and it is often not economically viable to change its use. The urgent challenge facing our industry is how to deploy and develop manufacturing systems that are flexible, quick to build, and less capital intensive. Advances in technologies and changing product requirements are significantly influencing companies’ approaches to facility design and deployment and the options available today. Typical considerations now include

• What is the role of disposables in facilities, and to what extent are they used?

• What are the true benefits of modularization, and where does it have the most impact?

• Is continuous processing an option, and if so, where and how should it be deployed?

• Should underused legacy facilities be replaced?

(Click to enlarge)

In this and subsequent articles we will address those issues. Here, we review optimal strategies for using disposables in hybrid facilities (a mixture of stainless and disposable technologies). In particular we examine the costs of such facilities, their scalability, and their advantages over a reference stainless steel facility.

Hybrid Disposable Manufacturing for Cell Culture

The basis of this analysis is a platform monoclonal antibody (MAb) manufacturing process (Table 1) with an expression level of 5 g/L and an overall yield of 51%. The goal is to manufacture ~450 kg of bulk purified product using 6,000 L of installed bioreactor capacity. Table 2 lists the exact configuration. The hybrid facility uses a mixture of proven commercially available disposable technologies and stainless steel equipment (Table 3). Questions to be addressed are

• What is the best configuration for a hybrid facility — multiple 1,000-L or 2,000-L bioreactors?

• What harvest configuration should be used in terms of pooling bioreactor harvests?

• How does the best hybrid option compare with stainless steel when changing facility use?

Table 1: Process details (Click to enlarge)

Table 2: Scenario configuration (Click to enlarge)

Table 3: Hybrid disposable options (Click to enlarge)

To answer those questions, we consider the option that gives the best return on investment. First, we evaluate the scenarios in terms of CoG and more rigorous approaches that take into account cash flow and risk (see “Measuring the Cost” box).

To carry out the analysis, we used the commercially available BioSolve Process software package (Biopharm Services). The software includes standard cost data provided by vendors, engineering companies, and end users (all data updated annually) and was used to set up the process options. It also includes an add-on module for carrying out more sophisticated return on investment (ROI) and net present value (NPV) analyses. We evaluated five scenarios. Key assumptions used for the ROI and NPV analyses are

• spending profiles capital project: stainless steel over four years (10%, 40%, 40%, 10%); disposable over three years (23%, 57%, 20%)

• discount factor of 15% used in the NPV calculation

• production up to 2020

• sale price constant per dose.

Simple CoG Analysis

Table 4 shows key results. From a CoG perspective, the results are interesting because scale-out options for the hybrid facility based on the 1,000-L bioreactor (scenarios 2 and 3) are most expensive, followed by the stainless steel and 2,000-L options (scenario 5). The lowest CoG is achieved by running 3 × 2,000-L bioreactors and harvesting all bioreactors together. The 3 × 2,000-L bioreactor scenario shows the lowest consumable cost among the hybrid options. Although consumables are more expensive here than in the stainless case, those costs are more than offset by cost reductions in other areas, particularly in terms of capital cost. Our scenario analysis confirms the thesis that as you increase the use of disposables, you are moving fixed up-front costs to activity-based costs (you only spend the money when you need to manufacture). This shift in cost structure has implications in terms of the effect of facility use and risk. A detailed discussion of facility use will be the subject of a later article.

Table 4: Scenario capital and CoG (Click to enlarge)