Supplementary Material for Allogeneic Versus Autologous Stem-Cell Therapy: Manufacturing Costs and Commercialization Strategies

METHODOLOGY

Leaders in the fields of stem-cell regulation, manufacturing, and commercialization were interviewed to establish the following:

• What a large-scale manufacturing process would be for an allogeneic therapy with stem-cell expansion and an autologous therapy with stem-cell expansion

• The cost of each component of the manufacturing process

Selected individuals were sent an email requesting an interview. A total of 186 emails were sent, resulting in 32 individuals ultimately being interviewed (10 face-to-face, 19 by phone, and 3 via email). Interviews did not follow a rigid question format. The following four groups were interviewed:

• Experts in the regulation of stem-cell therapies in the UK and US

• Senior managers at leading stem-cell companies in the UK

• Prominent academics and clinicians focusing on stem-cell therapies

• Specialist companies focusing on specific cost components, such as the shipment of stem-cell products

COST RANGE

A cost range for each component of the manufacturing process was established on the basis of minimum and maximum estimates obtained (see Table I). The cost range applies to both allogeneic and autologous therapy unless otherwise stated.

Table I: Cost range for each component of the manufacturing process for stem cell therapy. 1£ = US $1.6.

COST PER DOSE OF THERAPY

The following categories of data were calculated for allogeneic and autologous therapy:

• The cost to set up a manufacturing facility capable of manufacturing 2500 doses of allogeneic and autologous therapy a year (see Table II).

Table II: Cost to set up a manufacturing facility capable of producing 2500 doses of stem-cell therapy a year. 1£ = US $1.6.

• The cost to manufacture 2500 doses of therapy a year (see Table III). This calculation did not take into account the cost of setting up the manufacturing facility itself. The figure obtained was divided by 2500 to obtain the manufacturing cost per dose of therapy.

Table III: Cost to manufacture 2,500 units of stem cell therapy a year, 1£ = US $1.6.

• The cost to manufacture 2500 doses of therapy a year factoring in the cost of setting up the manufacturing facility (see Table IV). The calculation entailed dividing the cost to set up the manufacturing facility over its lifespan (i.e., 10 years). The manufacturing cost per dose of therapy was finally calculated.

Table IV: Cost to manufacture 2500 units of stem cell therapy a year factoring in the cost of setting up the manufacturing facility, 1£ = US $1.6.

ASSUMPTIONS UNDERLYING THE ANALYSIS

• To meet the UK demand for an unspecified medical condition, the manufacture of 2500 doses would be required annually.

• Each patient would receive one dose.

• One therapeutic dose wouldcontain 10⁸ mesenchymal stem cells (MSCs) and would take three weeks to culture using media and growth factors. MSC therapy was used in the analysis because MSCs are expected to become a principle source material for cell-based therapies. MSCs are straightforward to obtain from patients by bone marrow biopsy, relatively easy to culture expand, migrate to areas of inflammation and injury, and are immunoprivileged (1–4).

• It would be possible to use an automated cell-culture process to produce both allogeneic and autologous therapy. It was assumed that the automated cell-culture process would be able to run cell lines from multiple patients simultaneously to make automated autologous therapy production possible.

• Four automated cell-culturing machines would be needed to manufacture 2500 doses of therapy per year.

• For allogeneic therapy, 10 potential donors would be screened and tested to identify a donor with high-quality MSCs. This donor's MSCs would then be used to produce a cell-bank system, that would be viable for 10 years. The cell-bank system would consist of a master cell bank and a working cell bank. Each vial from the working cell bank would produce a batch of 100 doses of therapy. For autologous therapy, each patient would need to undergo donor screening and testing.

• For production of autologous therapy, donor material would be harvested from patients at UK hospitals and transported to the manufacturing facility. It was assumed that 10 leading hospitals across major cities in the UK would be able to provide national coverage of stem-cell treatments to the population for the unspecified medical condition. Donor material from approximately 16 patients would be shipped from each hospital once every three weeks to the manufacturing facility. This would allow 2500 doses of therapy to be produced per year.

• For production of allogeneic therapy, donor material would not need to be shipped from hospitals to the manufacturing facility because allogeneic therapy would be produced from the cell-bank system.

• Bone marrow cells would be harvested from donors via bone marrow biopsy. MSCs account for less than 1% of bone marrow cells (2). Therefore, bone marrow material obtained would need to be cultured to produce an adequate dose of MSCs for therapy. Purification and isolation of MSCs from bone marrow mononuclear cells would not be needed. The media and growth factors used would select for MSCs. Differentiation of MSCs into specific cell types would also not occur.

• For allogeneic therapy, 25 batches would be required to undergo release testing per year as each batch produces 100 doses. For autologous therapy, each patient's therapy is considered a batch in itself, so all 2500 doses of therapy would need to undergo release testing.

• The clean-room suite would have changing, preparation, processing, and packaging rooms. The manufacturing facility for autologous therapy would also have a specially designated room for release testing. It would hence be bigger than the manufacturing facility for allogeneic therapy and would consequently be more expensive to build and would have a higher cost of rent, utilities, and council tax. The specially designated room for release testing in autologous therapy would be needed because all 2500 batches of therapy produced a year would undergo release testing, whereas in allogeneic therapy only 25 batches would need release testing because each batch produces 100 doses. A clean-room suite would be expected to last 10 years.

• Each staff member would have a total cost of £100,000 (US $160,000) per year. Approximately 6–9 staff would be needed to manufacture 2500 units of allogeneic therapy per year and 9–11 staff to manufacture 2500 units of autologous therapy annually. Manufacturing autologous therapy requires more staff because significantly more donor and release testing must be performed.

• The stem-cell therapy would be administered intravenously. Each finished dose of therapy would be shipped fresh in a bag of sodium chloride solution ready for infusion.

• Therapy would be transported from the manufacturing facility to hospitals in the UK to be given to patients. It was assumed that 10 leading hospitals across major cities in the UK would be able to provide national coverage of stem cell treatments to the population for the unspecified medical condition. Approximately 16 units of therapy would be shipped every three weeks to each of the 10 hospitals located across the UK from the manufacturing facility. This would allow 2500 doses of therapy to be supplied each year.

REFERENCES

1. Y. Li and M. Chopp, Neurosci. Lett. 456, 120–123 (2009).

2. O.Y. Bang et al. Ann. Neurol. 57, 874–882 (2005).

3. L. Jackson et al., J. Postgrad. Med. 53, 121–127 (2007).

4. G. Chamberlain, et al., Stem Cells 25, 2739–2749 (2007).