Minimising costs and lead times, while also maximising supply security, is essential when choosing a cell culture media supplier; however, this must be balanced with robust quality standards, optimal consistency, and experienced support. This article outlines the key capabilities that developers should look for in a supplier to help achieve long-term manufacturing success.
Cell culture media is a significant driver of productivity within biopharmaceutical manufacturing processes. As it provides the essential components for cell growth and function, finding a suitable media formulation is a critical step during process development, and fundamental to achieving high titres and optimal product quality.
During media selection, there are two main choices for developers to consider: an off-the-shelf, catalogue product or a custom solution—either a customised catalogue product or a fully proprietary formulation. Although many media manufacturing considerations will be similar, if a custom solution is chosen, developers need to pay specific attention to considering how it will be manufactured at a commercial scale.
This can require finding a suitable external media manufacturer, as well as possibly qualifying a secondary or even tertiary supplier to proactively prevent any potential disruptions in supply. There are several options that developers utilising a custom solution can choose from—ranging from smaller, local suppliers to larger, global vendors with multiple manufacturing sites around the world.
When making this decision there are several factors that need to be considered—in particular, cost and lead times. While it is desirable to minimise these factors where possible, it is essential to do so without compromising on quality and consistency standards, supply chain reliability, and even provisions for the protection of intellectual property (IP). Choosing a supplier that has the experience and capabilities to efficiently resolve any media-related challenges can also help facilitate long-term manufacturing success.
To determine if a supplier can provide the required support and help minimise risks, there are several key areas to assess, including specific capabilities, infrastructure, and processes. By choosing the right supplier, developers can establish a dependable media supply, supporting them to scale up with confidence and mitigate the risk of costly delays arising in the future.
While there are many areas to evaluate during the selection process, there are a few that are pivotal to long-term success. In particular, ensuring regulatory compliance and safeguarding IP should be primary considerations for all developers.
Adhering to regulatory requirements is not only crucial to protect patient safety, but also to avoid incurring costly fines for non-compliance. Consequently, developers should prioritise choosing a supplier that has accredited manufacturing facilities and can provide documentation to validate compliance. When choosing a global supplier, it is particularly important for developers to verify that the supplier can meet the relevant regulatory requirements of the countries they are operating in.
IP protection should be another fundamental consideration. Proprietary formulations and other key process and product details are valuable information and keeping them confidential is essential for developers to protect their innovations and achieve their commercial goals. As a result, a supplier’s data security infrastructure should be a key topic of discussion during the selection and qualification process. This should include a dedicated cybersecurity programme and associated policies designed to mitigate data risks and respond to any threats.
Given the foundational role of cell culture media in biopharmaceutical production, maintaining quality and consistency is vital—particularly as production volumes increase.
To support seamless scale-up, it is paramount that a supplier has the necessary infrastructure, facilities, and procedures in place to help ensure quality and consistency are prioritised at all scales. Without these systems, inconsistency can lead to several challenges for developers, including reduced productivity, wasted resources, and manufacturing delays.
Although many different factors can give rise to media and process variability, by carefully evaluating four key areas, the risks can be greatly reduced, and challenges more quickly resolved.
Cell culture media formulations consist of a wide range of components that are sourced from suppliers around the world. As a result, maintaining the overall quality and consistency of media requires ensuring the quality of every raw material used. In particular, identifying the presence of trace element impurities should be prioritised. As key drivers of cell metabolism, even small amounts of trace elements—such as copper and manganese—can have detrimental effects on overall process productivity by impacting critical protein quality attributes. To minimise this risk, developers should look for a manufacturer that has an in-depth procurement programme and only sources raw materials from reputable and strictly qualified suppliers.
Once a supply of high-quality raw materials is secured, media suppliers should also have rigorous internal testing processes in place to help maintain quality standards. This includes measures such as accurately assessing all incoming raw materials. The use of techniques such as inductively coupled plasma mass spectrometry (ICP-MS) can help vendors identify and quantify any potential raw material impurities. In tandem with this, digital inventory management systems can be used to quickly highlight any variability. This can help enable the supplier’s quality teams to rapidly respond and prevent out-of-specification raw material lots from being introduced into the media manufacturing process.
Alongside routine raw material testing, analytical technology can also be leveraged to help optimise the media manufacturing process. Specifically, some suppliers will be able to offer services to help developers understand which trace elements their process or cell line is most sensitive to, and the optimal concentrations of these elements. Using these insights, developers can work with the supplier to implement proactive steps, such as dedicated raw material screening protocols, to control variability, lowering the risk of inconsistency and optimising productivity.
In addition to raw material impurities, contaminants can also be introduced into media during the manufacturing process itself. These unexpected contaminants are particularly critical to monitor as, in addition to causing process variability, they can also present potential safety concerns for the final biopharmaceutical product.
One potential source that should be considered is the contamination of animal origin-free (AOF) products with animal origin (AO) material. To reduce this risk, any sites that are manufacturing both AO and AOF products should have dedicated mitigation protocols in place. These should include measures such as maintaining a unidirectional flow of raw materials, material airlocks, integrated operating systems for real-time monitoring, and dedicated QC labs with separate material and waste flows.
Outside of AO/AOF cross-contamination, microbial testing is also central to controlling cell culture media quality—in particular, bioburden and endotoxin management. This is an area where choosing an established supplier can be advantageous, as it can leverage its expertise to detect and minimise endotoxin and bioburden risks. Developers should look for a supplier that can demonstrate that all raw materials are validated to their appropriate specifications and that the equipment utilised for production has been subjected to the necessary procedures. Diligent testing and sterilisation are especially crucial process steps that can help reduce the risk of variability-causing contamination being introduced.
Alongside carefully evaluating a supplier’s quality systems and manufacturing protocols, considering the level of supply assurance it can provide is also essential. To reduce the risk of supply chain challenges and any associated costly production delays, it can be beneficial to choose a supplier with a multi-site network that has built-in manufacturing redundancy. However, it is key that all processes across its locations are harmonised to enable equivalent products to be manufactured at each site. Site harmonisation encompasses the entire production workflow, so there are several areas where equivalency should be implemented.
Within a harmonised site network, raw material management is key. As previously mentioned, inconsistent raw materials can have significant effects on media performance. To mitigate this risk, suppliers should implement equivalency in their raw material processes, harmonising both sourcing specifications and supplier review protocols. Process and equipment equivalency is another area developers should verify with the supplier. In particular, suppliers should be able to demonstrate that manufacturing steps are mirrored, and that all manufacturing equipment can deliver comparable performance and is validated to the same standards. Quality assurance, control frameworks, and operating infrastructure should also be harmonised to help verify the same standards are achieved across locations. This includes utilising identical testing methods, equipment, cell lines, and specifications at each site.
Outside of media manufacturing, considering the overall cell culture knowledge and analytical capabilities of the supplier can also be advantageous. When issues such as batch-to-batch inconsistency arise during production it can often be difficult to identify the exact causes. However, an experienced vendor will often have the knowledge and the tools to carry out detailed investigations to help resolve any media-related challenges as efficiently as possible.
Support through manufacturing stability studies can also help give developers confidence in their formulation. Real-time stability testing of cGMP-manufactured media in the desired packaging configuration should be offered as a customisable service conducted under conditions and time points determined by the developer.
In addition to stability studies, an experienced media manufacturer may also be able to offer in-depth investigative analytical services to help developers resolve more complex challenges such as precipitates, extractables, and leachables. Using the outcomes of these investigations, developers can take steps to reduce the risk of similar challenges arising in the future—for example, by modifying their formulation or optimising media storage.
From regulatory compliance and IP protection to raw material sourcing and site-to-site harmonisation, there are many considerations developers need to take into account when selecting a media manufacturer. By working with the supplier to carefully evaluate and validate each of these areas, developers can determine if the supplier can meet their needs and begin the process of building a long-term collaborative relationship.
Although the evaluation process can require an initial investment of time and money, this can often be offset by the considerable benefits of working with a dependable media manufacturer. Through supplying high-quality and consistent media, alongside dedicated and responsive support, an experienced supplier can help developers streamline scale-up and accelerate their speed to market. Moreover, using its knowledge and capabilities, the supplier can also help quickly resolve any challenges that arise during manufacturing, helping developers maintain commercial success into the future.
After completion of his PhD at the University of Kentucky and a post-doctoral appointment at UC Davis, Chad has had professional stints across the bioprocessing industry. As a Senior Product Manager at Thermo Fisher Scientific, Chad is responsible for the Gibco™ Efficient-Pro™ medium and feed system and the customer-owned formulation product line.
