The Past And Future Of Managing Raw Material And Process Risks In Biomanufacturing

For many years, the biopharmaceutical industry has been predominately occupied by antibodies, which has strengthened our knowledge and expertise about how to successfully bring them to market. Now, pipelines are filling with innovative and potentially groundbreaking molecules tackling many unmet medical needs. As the complexity of these molecules increases, so do their development processes and the unique challenges that accompany them. The inherent vulnerability of these increasingly difficult processes makes them susceptible to even the slightest change, renewing anxiety over the long-standing issue of managing raw material variation and process risks.

With biologics predicted to contribute to 52 percent of the top 100 product sales by 2022,¹ we must ask ourselves: is the biopharmaceutical supply chain fit for purpose given the growth of our industry, and can we still use it to serve the millions of patients who depend on us? Answering these questions requires a look back at how far we have come in raw material supply management and what still needs to be accomplished to ensure the delivery of safe and effective drugs.

A Supply Chain Under Scrutiny

Supply chain visibility has always been an important topic of discussion in drug manufacturing, as any changes can lead to patient safety issues and extended plant shutdowns. And because too much or too little capacity can lead to unfavorable manufacturing economics, there is little slack in the overall supply chain, whether it is in terms of capacity or raw materials. As an industry, there have been many challenges when it comes to having enough capacity to meet demand and enough quality raw materials to supply patients with safe and effective drugs.

When issues do occur, they sometimes result in scandals that call into question whether biopharmaceutical manufacturers can effectively protect and manage the pipeline of drug supply funneling into the industry and a prompt a renewed focus on control measures. For example, when nearly 80 people were killed as a result of contaminated Heparin in 2008,² it triggered the refinement of supply chain controls and analytical assays to make sure that raw materials and their origin could be authenticated. The adulteration of infant formula and other food materials with melamine the same year also triggered a reevaluation of the supply chain to better understand how it was corrupted. These scandals raise difficult questions about the supply industry, raise doubts about whether the growth rate of the biopharmaceutical industry has outstripped the capabilities of the supply chain, and also increase regulatory scrutiny. Industry regulators encourage pharma companies to keep raw material quality in focus by making sure we have a supply chain appropriate for treating millions of patients.

The key to maintaining control is to create enough visibility so that we have the best chance of understanding the risks within our supply chains and can pave a clearer path toward constant improvement. One of the most critical challenges we face in this endeavor is raw material supply and raw material variation. If we can get these factors under a sufficient level of control, process development becomes much more straightforward, and as a result, we can achieve more robust processes.

Doing so requires us to address three key areas within our supply chains:

• Transparency – We must create visibility into supply chains so that people have the best chance of understanding the risks within those supply chains. There is a balance between too much transparency and too little. One customer may receive a change control notification (CCN) and see it as a very low risk while another customer may see it as a very high risk. How does a supplier assess the likely impact of changes when every customer has different expectations?
• Consistency – Small changes in raw materials, even though they remain within specification, can have a dramatic impact on manufacturing yield. Given the high price at which biopharmaceuticals sell, the economic consequences of this can be millions of dollars lost. By improving raw material consistency, you can better control process variability. So how can we enhance the reproducibility of our products?
• Risk – Because of the types of products the biopharmaceutical industry works with, you may have only a single source for your raw material. If that supplier shuts down or runs out of material, you are faced with the possibility that you do not have the raw materials you need to produce your product, leading to delays and/or drug shortages. If you add a second source, you could potentially be creating more raw material variability. How can we balance and mitigate these risks in raw material supply?

It is when we begin to consider these questions that some of our biggest challenges — and potential successes — begin to present themselves.

A Continuum Of Challenges And Successes

The journey to secure a robust process necessitates a complex series of interacting choices about raw materials and their security of supply. Today we see a continuum of risk in manufacturing processes. At one end are high-risk processes that were often developed using first-generation methods and much less knowledge than we have now. Those processes often include raw materials that are not ideal for biomanufacturing, such as serum, where the material is so variable you need to batch test every lot to ensure it works. At the other end is the promised land, where processes are developed by a thorough mapping of process space using raw materials from a diversified supply chain with multiple manufacturing lines, where the origins of variability are well understood and controlled.

Most processes today fall somewhere in the middle. Raw material variability and its effect on process outcome is reasonably understood, though our inability to completely control it means that, on some occasions, processes may fail at significant cost. Moving past this midpoint requires partnerships with trusted suppliers who can deliver a high level of consistency and a two-way exchange of data. It is particularly important suppliers get insight into exactly how raw materials impact processes, as this allows them to focus on the most important factors that contribute to process success. It also necessitates a toolkit that allows you to deliver process robustness and a significant degree of control over how variability with your supplier contributes to variations in your manufacturing process.

Raw Material Supply

Achieving greater continuity and security with raw material supply requires several key elements currently in practice in the industry:

• Supply chain mapping – Creates transparency in your supply chain, so you can see its vulnerabilities (including where key raw material suppliers converge) and assess risk.
• Raw material characterization – Uses analytical techniques to understand the key characteristics of a raw material and, ultimately, how they contribute to process quality.
• Raw material control – Turns characterization data into tactical management of how you can/should source raw materials.
• Inventory management and safety stocks – Secures and stabilizes inventory levels and costs to mitigate the risk of sudden disruptions; also establishes mutually beneficial terms for a healthy partnership and continuously improving quality measures, communication, and transparency.
• Second suppliers – Achieves a greater level of security, albeit sometimes at the cost of more raw material variation.

While many suppliers are increasingly focused on controlling raw material risk and securing supply, supply chain controls, safety stocks, and business continuity plans only go so far. What can the industry do to make ourselves resilient to raw material variability?

Raw Material Variability

Suppliers are increasingly applying Quality by Design (QbD) to create a smart process design that minimizes the impact of raw material variability. In particular, some major suppliers have used QbD to produce better, more predictable single-use film, which is a reflection of the industry’s willingness to learn from some of its most challenging experiences. More consistent and predictable film properties are seen as key to increasing single-use technology adoption. However, while QbD is a valuable tool, you must obtain a substantial amount of knowledge about the raw materials going into your processes for QbD to be effective.

For example, while exploring the development process for chromatography resins based on agarose, a team at Cytiva spent a considerable amount of time and money understanding the physical and chemical properties of agarose and how it worked in the manufacturing process. While it may have seemed like an exorbitant investment at the time, it resulted in vital knowledge that helped Cytiva understand how the properties of agarose, combined with other chemicals, contributed to the quality of the end product. In particular, it allowed the team to tune the way those raw materials were used to produce an end product with varying designable properties in terms of chromatographic performance. This investment in raw material science is fundamental to the development of a strong product base, which is beneficial when dealing with subsequent manufacturing challenges. The knowledge collected offered Cytiva the confidence to institute a second source of agarose without concerns that the change would impact the functional properties of its customers’ products or the manufacturing process employed. Without the investment in raw material understanding and analytical capability, such a change would have been inconceivable just a few years ago.

So how can suppliers make it easier for process developers to gain a better understanding of raw material variation and what tools can they provide to do so? Process development often focuses more on exploring processes rather than raw material attributes and will often use a limited number of raw material batches with limited variability. Suppliers can help by providing samples of raw materials that cover the breadth of the specification space, allowing the full impact of raw material variation to be evaluated. As suppliers accumulate experience and develop greater insights, they can then also focus process development efforts.

Some raw material variations can be relatively benign, while others can have devastating impact. Suppliers’ judgements on these matters based on historic experience can be valuable in prioritizing what raw material characteristics process development teams focus on. As more batches of raw material are used over time, long-term trending based on supplier/customer partnerships offer considerable benefits, ultimately allowing processes to be modeled more accurately and raw material impacts to be understood in great depth. Control strategies based on the outcomes of this work can ensure processes not only remain stable, but also gain in efficiency.

Process Robustness To Variability

Figuring out how to build greater confidence in raw material control requires open communication between manufacturers about how a supplier’s products are impacting the quality of individual steps within a process. Most importantly though, as we look toward the future, raw material data must be moved into electronic form, so it is easily accessible in comprehensive, user-friendly databases. Achieving this allows us to understand the true impact of raw material variation on process outcome and quality and allows a depth of investigation that is impossible today with data scattered between many different systems with both customers and suppliers. While there are tremendous challenges in executing this, due to the sensitivities around data sharing and transparency, doing so would streamline all aspects of the process and have tremendous economic and quality benefits.

In the end, the challenges with raw material and raw material variability are not going to get better as long as the relationship between manufacturers and suppliers remains purely transactional. Both sides must collaborate and work toward a common goal with aligned incentives to control the effects raw materials have on the overall success of serving our patients.

1. EvaluatePharma, World Preview 2017, Outlook to 2022 — http://info.evaluategroup.com/rs/607-YGS-364/images/WP17.pdf
2. European Compliance Academy, Chinese Heparin Manufacturer Again Involved in Falsification and GMP Non-Compliance — https://www.gmp-compliance.org/gmp-news/chinese-heparin-manufacturer-again-involved-in-falsification-and-gmp-non-compliance