Avoiding Timing Delays in Biologic Production

A surge in the demand for a product, such as what was seen when AbbVie’s Humira (adalimumab) won additional indications from FDA, or negative opinion on the price of a medication, such as what occurred when physicians at Memorial Sloan Kettering announced in an academic journal in 2013 their refusal to prescribe Zaltrap (ziv-aflibercept) instead of cheaper alternatives for the treatment of chronic myeloid leukemia, are events that can cause capacity problems at biomanufacturing facilities (1). These examples of capacity disruptions caused by fluctuations in drug demand-peppered with some survey feedback from anonymous, C-suite level industry professionals-were highlighted in a new report from Patheon and ORC International focused on dealing with inaccurate forecasts for biologics.

According to the report, capacity estimations are usually decided between Phase II and Phase III clinical trials, and as one anonymous biotechnology executive observed, companies like to lock in commercial pricing at the Phase III stage-which can be a risky proposition when demand is still largely unknown (2).

Changes to a clinical development plan, such as the addition of new indications, may require additional trials and can be cost-intensive. Regional differences in how the drug is prescribed and accepted by medical professionals may also play into demand and, subsequently, may affect capacity forecasts. Thus, forecasting where a drug is likely to be used is as important as figuring out how much to make, the Patheon/ORC report asserted.

Inaccurate forecasts
The survey reported that more than half of its respondents said their company overestimates biologics demand forecasts by approximately 25%. This number may be even higher for all drugs (small- and large-molecule products); in 2013, a Nature Reviews Drug Discovery study concluded that more than 60% of companies miss their demand forecasts by at least 40% (3).

When companies cannot produce enough medication to meet demand, the share price of said drug can be dramatically impacted, disclosed an anonymous C-suite executive. Additionally, for orphan products, if demand is not met, an annulment of an orphan status could potentially occur, the report authors wrote.

Planning for actual demand
Production planning often needs to occur two years in advance, said the report, and long lead times contribute to market uncertainty, as many production variables can change over time. Adapting to future demand, especially in the case of an expedited approval, is “currently not executed well,” the report authors stated. The process has to be commercially capable, noted an anonymous executive quoted in the report, and there is more pressure for process characterization early on in the scale-up of expedited products.

Patheon/ORC concluded that outsourcing to contract development and manufacturing organizations (CDMOs) is the best way to help companies manage demand and capacity fluctuations, especially when CDMOs are incorporating strategies such as single-use components, dual sourcing for materials, the parallel operation of bioreactors (known as “multiplexing”), and the incorporation of modular design into facilities.

Although the benefits of outsourcing were well represented in the report, concerns of biotechnology manufacturers about keeping intellectual property secure and the potential problems with scale-up or technology transfer that can occur were not mentioned. Additionally, the benefits of producing biologics through a hybrid approach or through an exclusively in-house model were not described.

References
1. H. Kantarjian, Blood 121 (22), pp. 4439–4442 (May 30, 2013).
2. ORC International and Patheon, “Implications of Inaccurate Forecasting on Biologics Drug Substance Manufacturing,” White Paper, http://www.patheon.com/en-us/Ideas-in-Action/Material-Details?materialId=59, accessed on June 7, 2016.
3. M. Cha, B. Rifai, and P. Sarraf, Nat. Rev. Drug Disc. 12, pp. 737–738 (2013).