[Vaccine-manufacturing] Vaccine Manufacturing Know How

Kristopher Howard khoward at nrlsolutions.com
Mon May 3 21:07:12 PDT 2021


I felt like there wasn’t enough out there in the general media about vaccine manufacturing know-how, so I decided to write a LinkedIn Article about it.  I’ve copied a link here in case you are interested.  I’ve drawn on my nearly two decades of doing technology transfers and likened it running a 3-Star Michelin Restaurant as this is one of my favourite analogies these days.  I hope you enjoy.

https://www.linkedin.com/pulse/what-do-vaccine-manufacturing-top-restaurants-have-common-howard <https://www.linkedin.com/pulse/what-do-vaccine-manufacturing-top-restaurants-have-common-howard>

What do vaccine manufacturing and top restaurants have in common?... Know-how which is difficult to transfer.
	• Published on May 4, 2021

Kristopher Howard
Global Vaccine and Pharma Manufacturing Consultant - advising companies, NGOs, and governments
5 articles

The world is currently looking to expand access to covid vaccines, and increasing manufacturing capacity seems the obvious solution. In this search for capacity, one hotly debated subject is removing IP barriers to increase the number of firms making vaccines through tech transfer. However, another term, "know-how," is also being used, which is hardly ever explained, especially within the context of IP. Therefore, I want to offer the reader a look at what "know-how" in the context of vaccine manufacturing really is.

To aid us in the discussion, let's use an analogy. Suppose you have a wonderful experience at a 3-Michelin Star restaurant and decide you would like to recreate it. If you went into the kitchen and convinced the staff to give you the recipe, you probably wouldn’t have a hope of recreating that meal. Additionally, with just a recipe, you most certainly wouldn't be able to start and run a 3-Star restaurant. Even if you were an experienced cook, the “know-how” needed to recreate that same experience is much deeper than obtaining written instructions on how to do so. It requires both tacit and explicit knowledge.

Tacit - intuitive knowledge and know-how rooted in context, experience, practice, and values (i.e., information best shared via watching and doing.)
Explicit – codified knowledge found in documents, databases, etc. (i.e., information readily shared via a written form.)
There are approximately 135 3-Michelin Star restaurants among countless other global eateries, and the list is by no means static. Some restauranteurs and chefs strive their entire careers to achieve that status, and many never do. Running such a high-caliber establishment requires highly skilled financial management, staff recruitment, training and retention, the ability to source the best ingredients from a select group of purveyors, staying abreast of the newest Michelin rating criteria, providing impeccable service and dining atmosphere, and last but not least, out of this world food each and every time. In short, it requires the confluence of many highly experienced and skilled specialists all working in concert. This is the same with the production of vaccines.

Most technology transfers require staff from a “sending site” where the product is already being produced to guide, teach and support staff at a "receiving site ." The teams work together to supply a given product at the required quality, quantity, and price completing the transfer in the expected timeframe and at the expected cost. This invariably requires the transfer of both tacit and explicit knowledge. 

Explicit knowledge is much more than just patents.

Much of the discussion today about technology transfer focuses on explicit knowledge and, in my opinion, not enough on tacit knowledge. Furthermore, a disproportionate amount of time is spent talking about patents. While patents are critical legal enablers or barriers, in reality, they represent a small portion of the overall explicit knowledge required for technology transfer. This is true even for new and novel vaccines.  

Simply having the patented information available for a vaccine production process is not enough for a company to make a product. Vaccines are not like small-molecule pharmaceuticals. A high-school student can fully characterize the synthesis and potential impurities when making generic aspirin on a sheet of paper. Many even synthesize aspirin as part of their chemistry lab class, which is not possible for biologics or vaccines. In fact, there is no such thing as a generic vaccine. That is to say, there is no way to make vaccines "identical" to ones made in another facility (this may be less true for mRNA vaccines). Most vaccines are produced in living cells via synthesis pathways that are rarely completely understood. Therefore, their purity or efficacy can't be wholly determined using analytical lab tests. The best-expected outcome is to make a "similar" vaccine product with a comparable safety and efficacy profile to the originator vaccine. But even this similarity must be determined by clinical testing in humans (often reduced compared to the original trial scope). 


Even though the processes to make mRNA vaccines have often been described as "chemical type reactions," they are complex and require the handling of sensitive biological material. For example, they require living bacteria cells to propagate DNA and biological processes to use that DNA to make the RNA needed for the vaccines. It is also important to note that these vaccines have never been commercialized before Covid. Therefore, there is a relative lack of global infrastructure and expertise in industrial-scale production of mRNA material compared to more traditional vaccines. Additionally, their final formulation and filling steps are very similar to traditional vaccines and are every bit as complex. According to Pfizer's president of global supply in a CNN interview, the challenges in producing the lipid nanoparticles at a large scale are far from trivial.

From 2006-2016, WHO executed the Global Action Plan (GAP) for pandemic influenza preparedness. The goal of the GAP program was to help enable the world to produce enough pandemic influenza vaccine in the event of a pandemic. To achieve that, GAP set out to motivate and capacitate more vaccine manufacturers to produce influenza vaccines. The egg-based inactivated influenza vaccine (IIV) that many of those manufacturers used was totally unencumbered by patents. Yet, many of the manufacturers who chose to make an IIV still required training and technical support. Therefore, WHO set up a vaccine technology hub located at the Netherlands Vaccine Institute to provide that technical support for those who needed it. Patents weren't the main obstacle for these GAP program participants; know-how, both implicit and explicit, was.

Tacit knowledge is equally, if not more important, than explicit knowledge.

I’ve been doing vaccine tech transfers for nearly two decades. Before coming into the vaccine space, I spent the first year of my career doing a technology transfer of the API for a small molecule cholesterol drug. Since then, I've done multiple vaccine transfers: in high-income and medium-income countries and between sites owned by the same company and transfers to external companies. I can attest that none of them would have been successful by providing explicit knowledge alone. Furthermore, all required onsite collaboration and highly aligned incentives between sending site and receiving site staff. 


Implicitly we understand this. We know that a detailed recipe and video of a chef making a dish will not guarantee your meal will be as good as the one you saw on TV or had at a restaurant. So much of how well the food turns out depends on the training and experience of the cook. It also depends on how often they have practiced making that dish. The technical baking challenge in every episode of the Great British Bake-Off is dedicated to exploiting this fact to produce an entertaining and often comical delineation between the contestants.

The best means of transferring tacit information is for sending and receiving site staff to spend time working together, in person. This is why apprentice systems, including ones for chefs, have existed for centuries. Ideally, receiving site staff would first go to the sending site to learn more about how the process works there. However, the more important and long-term obligation is for sending site staff to be at the receiving site. Sending site staff may be onsite for weeks or months at a time to mentor and teach the receiving site staff as they first prepare and then start up production of the new product. Problems and issues will arise. Having someone experienced in dealing with these or at least knowing how serious the issue is done most effectively in real-time and in person.

We have to look no further than the recent troubles sparked by failed batches of the J&J Covid vaccine at Emergent’s Bayview plant for a real-world cautionary tale of the difficulty of technology transfers. The trouble began when human error resulted in roughly 15 million doses of the J&J vaccine being wasted. The solution initially proposed was to have J&J take over management of the site, which would increase the amount of tacit know-how onsite. The facility would also stop producing AZ vaccine, which would lower the amount of know-how the staff had to acquire and apply successfully in the field. Note that the solution wasn't simply to retrain operators on procedures. This is because throwing more explicit information at people was unlikely to stop the same or similar problem from happening again. In the end, even these measures weren't enough, and the facility has been forced to halt all production due to additional critical quality system deficiencies recently found by the FDA

So why did this happen? Emergent CEO Robert Kramer framed it this way:

"We took on that Herculean task of progressing Bayview from a facility originally designed to develop and manufacture 50 million doses of a single influenza vaccine to one capable of producing hundreds of millions of COVID-19 vaccines. Everyone should keep in mind that this rapid scale of manufacturing had never been done before. We took a process that normally takes years and condensed it into months. We didn't flinch at that challenge because that's what this company was built for. We take on public health challenges that others won't."
If this lack of know-how can happen at a company built for pandemic response, with copious federal government support, located near sources of experienced workers, and with pre-existing FDA approval, it can certainly happen in lower resource settings.

Why is it so important for real-time support?

You have watched the video dozens of times and re-read the recipe just to be sure, but for some reason, after multiple attempts, you still can't get your soufflé to rise. Even if your favorite YouTube chef replied to your questions, your souffle is more likely to rise next time if that chef was standing next to you as you cooked. 

 Since it is impossible to use clinical testing to check the safety and efficacy of each vaccine batch, it is of utmost importance that the production process is as identical as possible between batches. Thus, the industry standard is to ensure the quality of the product by carefully selecting and then closely monitoring and controlling a wide array of production process parameters during manufacturing. As a result, vaccines are considered to be as safe and effective as those tested during the clinical trials provided: 1) the production process stays within its allowed limits, and 2) the final product passes a set of rigorous analytical tests. In industry parlance, this is referred to as "the process being the product", – but controlling the process within such tight parameters is challenging.

Consequently, hundreds or thousands of processing parameters must be monitored and controlled during vaccine production. Having someone experienced with this production process onsite in real-time to help sort through any deviation in those parameters is vital to a successful technology transfer. This is especially important when transferring a product to a facility that isn’t identical to the sending site or when differences exist between corporate or country cultures. This form of continual face-to-face training via discussions into why the process runs the way it does and troubleshooting issues as they come is the best way to transfer tacit knowledge to receiving site staff. Vaccine manufacturing, especially for Covid vaccines, is a high-stakes undertaking where a single batch can cost millions of dollars and protect millions of people. Therefore, it is essential to ensure those entrusted with making them are given the know-how needed to deliver as many as possible. Tech transfer is more than providing written instructions; it is about transferring experience.

So the next time you are confronted with the concept of vaccine manufacturing know-how and want to wrap your head around the complexity involved, simply ask yourself, “why don’t more 3-Star restaurants franchise?”

Those of us who have done vaccine technology transfers know all kinds of crazy things happen while executing them. Relay your favorite (or most unbelievable) story about doing one in the comments below.


Thanks

Kristopher Howard
NRL Enterprise Solutions
khoward at nrlsolutions.com <mailto:khoward at nrlsolutions.com>

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