A variety of factors have caused shortages in the marketplace for vaccines, but outdated manufacturing processes and lack of characterization stand out as some of the most prevalent, if not correctable, factors. Regulators across the globe and manufacturers are searching for ways to stabilize vaccine supplies.

As the Chief Operating Officer at Takeda Vaccines, Rahul Singhvi is on the front lines of ensuring a stable supply of these important prophylactics.

“Vaccines are very complex and the manufacturing processes that are used to make these vaccines are sometimes very old,” he said. “The regulatory burden to support upgrades to the processes to make them more cost effective or to increase capacity has limited the extent to which manufacturers have pursued these improvements.”

The reason for this lies not only in the complexity of the product but also the failure to take advantage of better analysis tools. Without comprehensive analytical tools, he said, “it becomes very difficult for a manufacturer to upgrade a process and take the risk of the product not changing on them in terms of its safety characteristics or its efficacy. And because of that risk, manufacturers tend to leave the process alone.”

Singhvi will discuss the complex issue of vaccine shortages and offer solutions at the 2014 PDA Annual Meeting in San Antonio, Texas (Opening Plenary Session, 8:45 a.m., April 7).
In Singhvi’s experience, the problem of vaccine supply limitations is more of an issue in the United States and Western Europe.

“Other manufacturers in countries like India and China have created manufacturing processes that are more productive; however, they don’t have the clinical data and the regulatory wherewithal to launch those products in countries like the U.S. or Western Europe,” he said.

But even if the problem is restricted to the United States and Western Europe, how can companies address these manufacturing shortfalls and ensure stable supply of product?

The answer, Singhvi said, lies in improved characterization of the product.

“These days there are much better analytical tools that are available that can do more in-process testing and understand the nature of the product,” he said. “And by having better characterization of the product that can also enable analytical comparability and provide a pathway for continuous improvement of the manufacturing process over time.”

These new analytical tools include the following, according to him.

• Cryo-electron microscopy: This process can be used for generating reconstructions of particles to build a 3-D model of the particle.
• Biacore®: This tool allows for analyzing antigen epitopes.
• Mass spectrometry: This tool allows for analysis of the composition of impurities.

These enable manufacturers to build quality into the process, providing “body of information” that shows if the various lots being produced are similar.

“And that helps everybody in moving forward in terms of making processes more productive and reducing cost of goods,” he said. “Technologies that provide for better characterization of the product will ensure that different facilities are also producing the same product, so the regulators are going to be much more comfortable with approving those facilities.”

Supply Chain Challenge Also Key

Along with the manufacturing process itself, Singhvi pointed out the complex nature of the vaccine supply chain. Vaccines require a lengthy shelf life as well as cold chain as the products are vulnerable to degradation. This presents problems when product is shipped to or through various temperature zones.

“The second issue is that the number of quality control tests that one has to go through in order to release a vaccine lot is fairly large,” he added. “Hundreds of tests are needed to release a lot, and when I say hundreds, I mean from raw materials to the end product—the quality control tests could be several hundred. And in fact, the quality control testing can account for 70% of the manufacturing time. The requirement of these prophylactic vaccines to be safe puts an enormous burden of testing on each lot of vaccine.”

Yet, Singhvi understands the reasoning behind this regulatory burden.

“You want the regulators to ensure that the product that is going into a healthy person—in many cases, a healthy child—that it is absolutely not going to cause any adverse effect, so therefore, it is appropriate for regulators to impose those tests,” he said. “But it makes the supply chain extremely complicated.”

He went on to mention that it’s not like regulatory authorities such as the U.S. FDA are unaware of this burden. In fact, due to the threat of pandemics since the early 2000s, the Agency has allowed for the shortening of the cycle time in the event a vaccine needed to reach the market quickly. There are sterility tests available now that can potentially be completed within one week. Normally, sterility tests take about two to three weeks. These types of innovations are now trickling down into the regular vaccine market.

These innovations that resulted from the pandemic threats now allow “for the manufacturers to do more analytical and more characterization work [which] will help the FDA to then be more comfortable with maybe lesser tests over time.”

Overall, new innovations and improved technology go to the heart of Singhvi’s presentation.

“I do believe that technology has a role to play,” he said, emphasizing that these newer technologies are useful in the vaccine space since vaccines are low-volume products manufactured in a scaled down environment. In particular, he singled out single-use systems.

“In that kind of scaled environment, single-use technologies could be very valuable. That can allow for the supply of vaccines to be distributed so you could have multiple facilities that can give you continuity of supply. If one facility goes down, that doesn’t mean that you have complete stockouts. You can have several facilities producing the vaccine,” Singhvi explained.

Ultimately, he expressed that the use of new technologies in vaccine manufacturing will help ensure a more stable supply, reducing the threat of product loss and ensuring these medically necessary products remain available and continue to benefit patients.

About the Expert

Rahul Singhvi is responsible for global supply of Takeda vaccines. He has extensive experience in both vaccine development and manufacturing.