Optimal production decisions in biopharmaceutical fill-and-finish operations

Tugce Martagan,Alp Akcay,Maarten Koek,Ivo Adan

doi:10.1080/24725854.2020.1770902

Tugce Martagan, Alp Akcay + Show 2 more

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https://doi.org/10.1080/24725854.2020.1770902

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Abstract

Fill-and-finish is among the most commonly outsourced operations in biopharmaceutical manufacturing and involves several challenges. For example, fill-operations have a random production yield, as biopharmaceutical drugs might lose their quality or stability during these operations. In addition, biopharmaceuticals are fragile molecules that need specialized equipment with limited capacity, and the associated production quantities are often strictly regulated. The non-stationary nature of the biopharmaceutical demand and limitations in forecasts add another layer of challenge in production planning. Furthermore, most companies tend to “freeze” their production decisions for a limited period of time, in which they do not react to changes in the manufacturing system. Using such freeze periods helps to improve stability in planning, but comes at a price of reduced flexibility. To address these challenges, we develop a finite-horizon, discounted-cost Markov decision model, and optimize the production decisions in biopharmaceutical fill-and-finish operations. We characterize the structural properties of optimal cost and policies, and propose a new, zone-based decision-making approach for these operations. More specifically, we show that the state space can be partitioned into decision zones that provide guidelines for optimal production policies. We illustrate the use of the model with an industry case study.

Highlights

Biopharmaceuticals are complex molecules that are extracted from or produced by living systems, such as virus or bacteria
We develop a finite-horizon, discounted-cost Markov decision model, and answer the following research questions: How can biomanufacturers manage challenges related to yield uncertainty and freeze periods in biopharmaceutical fill-and-finish operations? What are the optimal production and inventory decisions for fill-and-finish operations? Can we generate guidelines that are easy to implement in practice and yet deliver optimal policies? How can we model and analyze the impact of freeze periods on the expected total cost in this setting? What is the additional cost of freezing production schedules, and how does this cost change with the length of freeze periods? By answering these questions using an optimization framework, we believe that biomanufacturers can significantly reduce costs in fill-and-finish operations
We focus on papers that are directly related to our research, and refer the reader to Yano and Lee (1995) for a comprehensive review on random yield models in inventory management

Summary

Introduction

Biopharmaceuticals are complex molecules that are extracted from or produced by living systems, such as virus or bacteria. These drugs are proteins, antibodies or vaccines, and are referred to as generation drugs produced by biomanufacturing technologies. Biopharmaceuticals are manufactured through a series of fermentation and purification operations This often results in active pharmaceutical ingredients or antigens, depending on the specific application context. The resulting product is called bulk material, and is stored in large quantities for further processing. The bulk material is filled into smaller vials or other forms of packaging during fill-operations. Freeze-drying removes all the liquid from the filled product, such that only a so called ‘cookie’ remains in the vial.

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