A platform process is a set of standardized protocols and reagents that can be used to support a variety of clinical molecules. Typically these protocols and reagents, including cell culture media and feeds, are standardized for a specific parental cell line such as CHO or NS0, and cell culture process, like batch, fed-batch or perfusion. Platform processes prove advantageous when it comes to implementing developmental improvements. An enhancement to the platform can be spread across multiple clinical molecules, improving an organization’s return on investment. However, if there is a problem with a reagent in a platform process, it has the potential to impact multiple molecules in the organization’s clinical pipeline. A number of risks are inherent to platform processes. They fall into three main areas: supplier risk, raw materials risk, and process risk.
When assessing the risks around suppliers it is important to consider the whole process, not just raw materials – everything from electricity to water can pose problems if the supply fails. The consistency of the supply depends on the continuity plan; what will happen if they fail to deliver? This is particularly important for biologicals, as many raw materials are not dedicated to the sector, and it is only a very small part of the suppliers’ business. A biologicals manufacturer will always have very low economic negotiation strength within the supply chain. Yet, if the supplier chooses to optimize its supply chain for another market, this may have an impact on the biological process.
For example, a few years ago a supplier of growth factor optimized its process for human therapeutics, which made up almost all of their sales. But it was also used in cell-based manufacturing processes, and this change had an impact on the potency of this product for these processes. This manufacturing change to the growth factor impacted both process yield and the final product quality profile, resulting in many organizations having to requalify the acceptance limits of their manufacturing process. This can be mitigated by looking closely at suppliers, and establishing just how much of their business is in the biopharmaceutical industry and, when possible, sourcing from suppliers that are focused on supplying the market.
With cell culture media, the problems are multiplied because of the sheer number of components they contain. Every single supplier is equally critical – if a formulation has 60 components and one is missing, the formulation has changed, and this will affect the process. Some media formulations have even more components than this – sometimes upwards of 100. This makes it a real challenge to keep track of all the suppliers and their capabilities.
Raw Material Risks
Once a raw material has been secured, the issue of its quality must be considered. For single chemicals, it is usually relatively straightforward to check they are what they should be, and that they are sufficiently pure. For others, it can be much more difficult. This is a particular problem for undefined components such as hydrolysates whose composition is naturally variable, even between batches from the same supplier.
Even with simple chemicals, problems can arise. Sodium chloride, for example, is common in cell culture media, but there are also very many, much larger volume uses of sodium chloride. In this case, trace element contamination can be a real issue with sodium chloride, and while you can ask the supplier for a dedicated line to give surety of quality, this is unlikely to happen. Quality is not the only issue – there is also availability. For example, at least 80% of the world’s supply of potash comes from a single mine in Canada and when the workers there went on strike, potash became increasingly difficult to source.
Another issue with raw materials is how they are handled. Some, for example, are hygroscopic, which impacts flowability. If they form hard lumps as they take up moisture, this can cause problems in production and cause delays. This can also change over time, so ensuring consistency is important.
When it comes to the process itself, it is essential to ensure it is robust. Are there any aspects of the other two risk areas – materials and suppliers – that can impact final product quality, contaminant profile, and process performance in terms of titre, yield and throughput? And are any specific facility requirements necessary? Some buffers, for example, have a high ethanol content, and the flammability has to be managed. Other processes use noxious acids so hoods and personal protective equipment is needed. These issues are magnified on scale up – 5ml of concentrated hydrochloric acid is not much of a problem, but when you work with 500 litres it becomes much more of a safety issue.
One way of managing the risks within a platform process is to develop a platform medium that contains as few components as possible. Every additional supplier is another potential break in the supply chain. As a result, SAFC has been trying to rationalize the media components by titreing them; the goal being to understand how essential they are to the cell culture process. Many components are added because of an idea that they might improve cell culture performance, but in reality at best they may give no improvement, and at worst can actually have a negative impact. The essential amino acids need to be there, as do a carbohydrate source, essential vitamins, at least one ion carrier and some salts. After that, all other raw materials offer diminishing value.
Another way to manage risk is to use as many chemically defined components as possible, by using alternatives to undefined components such as hydrolysates. Similarly, polymorphic components are best avoided, and polymers like polyvinyl alcohol where the molecular weight is variable can cause problems if there is a shift in the range of that molecular weight.
There are several questions that must be asked:
- Do you have SOPs in place for raw materials handling?
- Are they stored in GMP warehouses where temperature is mapped and monitored?
- Are the items validated? Validation of raw material packaging is crucial to prevent moisture uptake or leaks.
SAFC is also working on other risk mitigation strategies that are becoming more common across the industry, such as using high-throughput screening techniques for virus risk mitigation. The aim is to put together capabilities at the pilot scale and, ultimately, for commercial production. However, it is important that the components and formulations are amendable to be compatible with these new treatments. A good example is the introduction of 0.1µm filtration to remove mycoplasma contamination from incoming raw materials. We changed our hydration protocols so our media were amendable to this type of treatment. The strategy must often change to accommodate new introductions and developments.
Other treatments for incoming raw materials involve UV radiation, which will cause problems with any components in a medium that are sensitive to UV energy, such as the aromatic rings in amino acids like phenylalanine and tryptophan. This can be avoided by supplying the medium in two parts, one of which is treated with UV radiation, and the other is not.
Lastly, SAFC manages a supplier quality-management process. This means their products and processes are audited based on an assessment of their financial strength and also on how important SAFC is to their business. This allows SAFC to quantify an overall risk assessment strategy to help ensure continuity of supply. In theory, by reducing the variables over purity, contamination and product variance, the process performance should be more consistent.
More information on SAFC’s risk management capabilities