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Critical Steps in Upstream Manufacturing: A Risk Management Approach

Biotechnology companies involved in the production of biopharmaceuticals rely heavily on upstream manufacturing processes to create a high-quality product. Upstream manufacturing refers to the early stages of the manufacturing process, where living cells are grown and manipulated to produce the desired protein or molecule. These steps are critical to the success of the overall process and require careful attention to detail and risk management. In this article, we will explore the key steps involved in upstream manufacturing and how to control the risks associated with them.

Key Steps in Upstream Manufacturing

  1. Cell Line Development: The first step in upstream manufacturing is to develop a cell line that can produce the desired protein or molecule. This process involves selecting a suitable host cell, modifying its genetic makeup to produce the protein of interest, and optimizing its growth conditions.

  2. Seed Train Development: Once a suitable cell line has been identified, the next step is to scale up the production of the cells. This is done through a process called seed train development, which involves a series of small-scale cell culture vessels that gradually increase in size.

  3. Media Optimization: The media used to grow the cells is critical to the success of the process. It needs to provide the necessary nutrients and support the growth of the cells while also maintaining the stability of the protein or molecule of interest.

  4. Bioreactor Operation: Bioreactors are used to grow the cells on a larger scale. They provide the optimal conditions for cell growth and protein production, including temperature, pH, and oxygen levels. The bioreactor must be monitored and controlled carefully to ensure consistent and reproducible results.

  5. Harvesting and Purification: Once the cells have produced the desired protein or molecule, it needs to be harvested and purified. This involves a series of filtration and chromatography steps to remove impurities and concentrate the product.

Controlling Risks in Upstream Manufacturing

  1. Quality by Design (QbD): QbD is an approach that emphasizes the identification and control of critical process parameters (CPPs) and critical quality attributes (CQAs) throughout the manufacturing process. By identifying and controlling these parameters and attributes, companies can reduce the risk of variability and ensure consistent product quality.

  2. Process Analytical Technology (PAT): PAT involves the use of real-time monitoring and control of critical process parameters. This enables companies to identify and correct any issues as they arise, reducing the risk of variability and ensuring consistent product quality.

  3. Risk Assessment: Companies should conduct a thorough risk assessment of their upstream manufacturing process to identify potential hazards and control measures. This should be an ongoing process that is reviewed regularly to ensure that new risks are identified and addressed.

  4. Training and Personnel: Upstream manufacturing requires skilled personnel who are trained in the specific techniques and processes involved. Companies should ensure that their personnel are adequately trained and that their skills are kept up-to-date through ongoing training and development.


Upstream manufacturing is a critical component of biopharmaceutical production, and it requires careful attention to detail and risk management to ensure product quality and consistency. By focusing on critical process parameters and quality attributes, implementing real-time monitoring and control, conducting regular risk assessments, and ensuring personnel are adequately trained, companies can reduce the risks associated with upstream manufacturing and produce high-quality biopharmaceuticals.

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