Introduction

Biopharmaceutical companies have to manage complex supply chains to obtain the materials necessary to manufacture their products. One of the areas where supply chain management is critical is in the sourcing of raw materials for cell culture media. In many instances, companies will purchase a custom formulated dry powder media from a media supplier. In these cases, the biopharmaceutical company is relying on the media supplier to source the raw material components, however they will still need to audit the vendor and their supply chain management system. While the company may not be managing the raw material manufacturers directly, it is key that they understand their suppliers’ supply chain and have oversight.

Biopharmaceutical companies might also decide to directly source some of the most expensive or most complex media ingredients directly from raw material manufacturers. A company might choose to do this in order to receive better pricing and/or ensure quality or supply. These components commonly include growth factors or other supplements. Some examples might include recombinant proteins and soy or plant based hydrolysates.

Background

In the 1980’s and 90’s, changes occurred in cell culture that influenced the way media is now optimized and manufactured. One of these changes was the discovery of the risk of prions in bovine sourced materials, namely BSE. The discovery of BSE in the mid-80’s prompted the biopharmaceutical industry to begin to look for ways to eliminate serum from media formulations. After serum was removed, there was another push to remove all animal-derived components. The removal of animal components forced cell culture scientists to look for other ingredients that could be added to media to maintain cell culture health and productivity, thus increasing the number of ingredients and the complexity of the media formulation.

Coinciding with the desire to remove animal components was a growing interest and understanding of cellular metabolism and nutritional needs. This increased knowledge of cell health allowed scientists to experiment with different ingredients that could be used to offset the effects of removing serum and improve specific cell functions.

During this time, it also became essential to improve manufacturing, increase cell culture titer, and increase the amount of final product that could be derived per batch. These improvements were critical for expanding into many therapeutic areas. Cost and demand are important drivers in many products and increasing output helped address these issues. This focus on improving cell culture performance, coupled with a greater understanding of cellular metabolism, enabled further optimization of culture media.

The culmination of these changes was that cell culture media evolved to be highly optimized and complex. As the industry transitioned away from serum and animal components, the complexity of the formulations and the number of different required components grew. For example, classic media with serum that was used early in biopharmaceutical manufacturing would typically include 25-30 different components. Now a typical cell culture media contains 50-75 different components with more complex formulations reaching 100 components or more.

Why is Raw Material Sourcing Challenging?

There are several challenges that can arise during raw material sourcing. Many of these involve managing the supply chain to ensure supply and quality.

Complex Media = Complex Sourcing

With the high level of complexity and the large number of media components involved, a great deal of coordination and oversight is required. The availability, quality, and traceability of raw materials must be assessed and ensured. Global sourcing can complicate this task, particularly if raw materials are sourced from countries where manufacturing problems have occurred in the past and/or manufacturing quality standards vary.

Testing To Ensure Quality

Certain raw materials can be quite variable and may need to have a higher level of testing to ensure consistent quality. Another area where increased testing may be warranted includes raw materials that have a history of having been adulterated. Often fingerprint testing of the material can be conducted to ensure that the product is pure. Risk of contamination is another cause for further testing based on the relative risk that the raw material could introduce a contaminant. Deciding which components need a higher level of scrutiny and testing can be difficult and requires a detailed risk assessment.

Traceability

It is important to understand the role each company plays in the overall supply chain. A company must be able to identify and trace the material back to the original manufacturer and determine if there is a distributor or other intermediary in the chain. Traceability is important in maintaining lot-to-lot consistency, ensuring safety of the raw materials, and maintaining a consistent supply.

Successful Supply Chain Management

There is no question that sourcing raw materials for biopharmaceutical manufacturing is a demanding task. This assertion was confirmed when I interviewed several people who work in sourcing roles for biopharmaceutical companies. In these roles, they interact directly with media suppliers and raw material manufacturers to safeguard a consistent supply of raw materials. During the course of these discussions, I asked about their experiences and recommendations for success in these areas. I have included a summary of these suggestions below.

Implement a Risk-Based Approach to Supply Chain Management

It is important to analyze media components based on their relative level of risk. Once the level of risk is established, it is easier to decide the level of documentation, testing, and oversight necessary on a component-by-component basis. I have listed some factors to consider when evaluating risk below. Many of these factors can be understood through good supply chain traceability and understanding each component’s country of origin, the level of component complexity, and security of the supply.

• Country of Origin: A raw material will have a higher risk profile if it is from a country of origin where quality has been a problem in the past or where there are not clear standards or oversight on manufacturing and quality.
• Complexity: The complexity of the component including its ability to introduce a contaminant, inherent variability, a higher level of impurities, and difficulty in manufacturing warrants a higher risk. Animal sourced materials, growth factors, and supplements are often examples of complex media components with a higher risk profile.
• Availability: It is important to also consider how many suppliers manufacture a certain component and what is the security of that supply. An important question to ask is whether the product is interchangeable with products from other suppliers. If a component has only a few manufacturers or if the supply is threatened then it becomes a higher risk component.
• Assessing Quality: Assessing whether there are testing methods available to easily verify quality and purity of a product is an important factor in determining risk. If testing methods are not readily available or aren’t very good, then the risk level would be higher.

These questions and the level of risk assessed for each will help inform decisions about the kind of quality testing and quality agreements necessary, the need to qualify secondary suppliers, and the level of auditing required. The higher the risk, the more intense the scrutiny of the supply should be.

Take Care in Selecting Suppliers

A common theme that was shared in my interviews was the importance of taking special care in selecting suppliers. The overriding message was not to just consider cost, but also reputation and whether you think you will be able to work with the company to meet needs. In many instances, biopharmaceutical companies will be auditing their media supplier’s supply chain and ensuring that they have sufficiently audited their raw material manufacturers.

Some key questions to consider before entering a supplier relationship:

• What is the experience level of the supplier?
• Do they have supply chain traceability for components?
• Do they understand our needs?
• Are they flexible if I need a higher level of testing or documentation?
• How do they manage sub-suppliers?
• What countries do they source materials from and how do they ensure quality in global sourcing?
• Are they open about their supply chain management and risk based assessments? Also, are they willing to explain the rationale for these decisions?

 Establish Expectations Clearly Up Front to Eliminate Surprises

Develop a good working relationship with your supplier; this includes creating clear quality agreements. Both the customer and the supplier must be in agreement regarding required testing of the raw materials. These agreements should establish expected change control procedures, product notifications, and subsequent impact assessments. Informing suppliers of specific material quality expectations and apprising them of the ongoing monitoring plan helps prevents surprises. Stating clear expectations also makes it easier to address a problem when one arises.

It is important to note that most of the people I spoke with indicated that having a good relationship goes both ways. It should be approached as a partnership and if there is a problem, both sides work together to determine the issue and create a solution. Customers should view the relationship as long-term and that working in partnership will be substantially more fruitful. If you have selected your supplier well, they should be just as driven to find the solution to your problem as you are.

Good Communication Internally

Just like it is important to develop a good working relationship with your supplier, it is also important to implement good communication between internal groups that are involved in the qualification or use of the products. Good communication between your supply sourcing group, your QC/QA groups, process development, manufacturing, and clinical groups will go a long way to providing early alerts to potential problems. It is also important to let your suppliers know early if demand will increase. Letting suppliers know early about potential problems with the media will help them to identify the problem more quickly and early communication about increases in demand for media will help them work with their suppliers to ensure that there is no problem in sourcing needed raw materials.

One example highlighting the need for good communication is in bioburden. Individually, each raw material component can be within specifications, but when mixed together the total bioburden may exceed acceptable levels. It is important to discuss how various components, even when within specifications, may behave once mixed. There can also be unexpected impacts of material on final drug product quality, therefore ongoing monitoring and good internal and external communication is essential.

Reassess Risk Throughout Product Development

To reassess your initial risk analysis, use process development, scale up, and early clinical. New information will be regularly available and it is important to incorporate this learning into a revised risk analysis. In addition, as a product moves closer to commercialization, there may be business factors that will require reassessing your supply chain management system. It is critical that the process inform revisions to the risk assessments. For example, if a component shows a high level of variability during process development, consider removing the component or replacing it with another comparable but more consistent product.

Be Proactive in Dealing with Regulatory Expectations and Changes in Requirements

Try to see the writing on the wall. If you expect that there is going to be a special requirement or expectation from a regulator, prepare early and involve your supplier in that preparation. They will need time to ensure they can deliver on any changes that are required.

To Learn More:

If you want to learn more about good management of raw materials and the importance of having a well thought through approach when searching for a supplier, check out this webinar hosted by GE Healthcare Life Sciences

Five questions to ask before selecting a raw materials supplier

Do you know the critical factors that affect the success of biologics manufacturing?

Join us for a free webinar where we will discuss:

• Trends that are shaping our industry and why demands of raw materials management are on the rise

• Best practices in raw materials management including quality by design (QbD) approaches and component supplier management

• Five key questions to ask to help ensure that your cell culture products supplier meets your needs

These aspects of raw materials management will be discussed in terms of the recent acquisition of HyClone™ cell culture by GE Healthcare.

There will be a live Q&A session at the end of the webinar.

Register today:

https://event.webcasts.com/starthere.jsp?ei=1043896