The 19-billion-dose challenge

Before the pandemic, global demand for vaccines was 5 billion doses per year. This included vaccines for influenza, measles, chickenpox and many other diseases. Taking into account the much-needed Covid-19 vaccines, the new estimated global demand for all types of vaccines in 2021 is 19 billion doses – almost four times the demand we experienced just two years ago.

This huge increase in global capacity requires detailed coordination across the entire value stream, end to end, to ensure that critical raw materials are available and bottlenecks are resolved, as well as scaling up potentially risky new technologies. In this article, I will discuss how lean thinking and practice can help us succeed at this crucial moment.

There are two main challenges we need to tackle at this stage of the fight against the pandemic. I describe them below.

 

Challenge #1: Develop and approve an effective vaccine with high-volume processing capability (complete and ongoing)

Before Covid-19, the shortest time we had historically achieved to develop and obtain approval for a vaccine was five years, for the Ebola vaccine developed by Merck. Before the Ebola vaccine, it typically took 10 to 15 years for a vaccine to be developed and approved. It was not until 1945 that the first influenza vaccine was licensed for civilian use in the United States – 27 years after the 1918 flu pandemic.

The development and approval of the first Covid-19 vaccine took 11 months, breaking all records. Fifteen months after the start of this pandemic, eleven different vaccines have already been approved worldwide, with more than 75 undergoing clinical trials.

Companies such as Pall Biotech, part of Danaher Corporation, were able to contribute successfully to this initial vaccine development challenge using the lean principles and practices that had become embedded in their organizational DNA over many years of activity.

 

Challenge #2: Develop and expand global vaccine manufacturing capacity (in progress)

From a process development standpoint, before Covid-19 the vaccine industry took up to five years to build enough manufacturing capacity across the entire supply chain to produce an actual vaccine. And it could take two years to transfer additional production to other contract manufacturing organizations (CMOs).

The end-to-end manufacturing and supply value streams for the Covid-19 vaccine are a complex chain of processes that stretches around the world. More than a hundred types of raw materials and components are needed to produce and prepare one dose of vaccine before it is injected. Vaccine production processes have a long history of highly complicated and typically non-standardized flows.

The three high-level steps in vaccine manufacturing are upstream processing, downstream processing and fill-finish. Upstream processing is where the cell culture is developed, grown and harvested after being induced to produce the target drug substance. Downstream processing takes the drug substance and purifies it to a specific level using various techniques. Fill-finish mixes the purified drug substance with other ingredients to create the actual vaccine, then doses the vaccine into vials and finally packages the final product for shipment.

Most of these manufacturing steps must take place in tightly controlled cleanroom environments that are highly regulated by government agencies. And these manufacturing steps take place at hundreds of CMO sites around the world, with thousands of quality control checkpoints throughout.

 

Risks and gaps

In March 2021, the United Kingdom and Chatham House co-sponsored the Covid-19 Vaccine Manufacturing and Supply Chain Summit, with participants from across the end-to-end supply networks. A summary of the discussions held at the Summit can be found here (in English).

The Summit highlighted several risks and gaps in the current vaccine supply and manufacturing landscape.

The total lead time for a single batch, from start to finish of manufacturing, is up to 120 days, which makes it difficult to speed up the process to meet growing demand. With more than 100 ingredients, components and packaging materials required for vaccine production, if any key material or quality data is missing or insufficient, entire batches in process can be lost.

Critical equipment with very long lead times to build and qualify is needed at several steps, with numerous high-risk technologies being deployed for the first time. Forecasting of equipment to be purchased is also highly chaotic – it is not unusual for a supplier to receive an order from a CMO for a new piece of equipment that will consume months of the supplier's capacity to design, build, qualify, deliver and install, with little or no visibility of the order.

For the upstream process of the value stream, supply risks include bioreactor bags, single-use systems and cell culture media. For the downstream process of the value stream, there is a constrained supply of filters and gamma sterilization. In fill-finish, glass vials remain a critical supply item due to boron constraints. There is a limited supply base to provide the materials for much of the vaccine's bill of materials (for example, one boron mine in California supplies 40% of glass vial manufacturers).

With regard to planning and human behavior, there is a tendency in our human planning and forecasting systems to want higher inventory levels as a reaction to the uncertainties on the horizon, as well as because of global trade issues. Inventory management is also highly variable – manufacturers are over-ordering to protect their interests, especially for vital supplies such as glass vials.

So where does lean thinking fit into this chaotic situation? This article will discuss how lean can help address the main difficulties we may encounter in the vaccine manufacturing process, grouped into three areas – production improvement, flow management and risk mitigation.

 

Production improvement: Increasing process capacity

Understanding the types of capacity

The priority is to gain an understanding of the capacity of each of the processes in the value stream. Capacity can be defined in different ways, but the discussion here will focus on three types of capacity – planned capacity, actual capacity and installed capacity.

For example, suppose Process A has a planned run time of 16 hours per day and 100 parts per hour (36 seconds per part), taking into account the calculated allowances for yield loss, changeover time and other minor interruptions. Process A has a planned capacity of 1,600 parts per day. Actual capacity is the performance of the current process, which takes into account all delays, yield losses, lost time, unused operating hours and much more. The daily performance of Process A is 1,200 parts per day (48 seconds per part) – the actual capacity, which is 75% of planned capacity. In addition, the installed capacity of Process A, when we remove all interruptions, is actually 125 parts per hour (29 seconds per part), or 2,000 parts per day. Process A is therefore using 60% of its installed capacity.

Countermeasures to improve capacity

Once there is a better understanding of the capacity gaps, there are many levers we can pull to increase output from existing processes, which typically include the more costly and time-consuming measures at the bottom of the list:

• Reduce lost time in the existing process (increase efficiency = more output).
• Reduce part-to-part cycle time in the existing process (increase capacity = more output).
• Make a low-cost investment in the main bottleneck (increase capacity with less investment = more output).
• Reconfigure another underutilized process for flexibility (flexible capacity with more investment = more output).
• Design and install a new flexible process (high capital expenditure = more output).

 

Flow management: Improving end-to-end visibility and reducing system variability

Without close collaboration, frequent communication and trust across the entire end-to-end value stream, the risk of demand amplification at each stage of the process is dangerously high. As demonstrated years ago by Jay Forrester of MIT, and simulated in the classic Beer Game, the bullwhip effect must not be ignored in supply chain planning.

In the simulation and in real-life studies, demand forecasts at the initial processes in the end-to-end value stream can be more than six times higher than actual consumer demand. The reasons for this bullwhip effect in orders can be attributed to several factors, including order rationing, information delays, limited information sharing, stockpiling, batching rules and much more.

For the Covid-19 vaccine value stream, it will be essential for organizations to come together to create a shared visual dashboard of global capacity and critical supply planning to ensure that the right materials reach the right place at the right time. Think of it as a global obeya or visual management space. There is no point in having a few glass vials reserved for an unproven vaccine in early clinical trials when another vaccine that has just been approved has a shortage of the same glass vials.

And the same logic applies to how critical long-lead-time equipment will be purchased and installed for production processes in the right place at the right time. Many equipment suppliers are already fully booked with work until 2022, based on uncertain forecasts and vaccines. The industry cannot allow all the uncertainty to paralyze execution, adding to the variability with reckless management practices.

 

Risk mitigation: Managing new innovation processes and closing knowledge gaps

The development of the Covid-19 vaccine has shed light on recent innovations and also highlighted opportunities for future areas of innovation. The evolution of single-use systems over the last decade has been a major advance in the current environment, greatly improving lead time for vaccine processing by switching from large-batch vessels with limited flexibility to smaller-batch disposable systems with capacity for mixed substances.

From a materials standpoint, suppliers have also been working on alternatives to traditional glass vials, developing vials that use less or no boron, an element that is currently scarce. Some of the current vaccines can use these new vials, which places less burden on the traditionally constrained vial supply stream.

By analyzing the end-to-end process and matching supply to global capacity, organizations will be able to identify processes that need innovation as a countermeasure to existing supply risks. Supply risks can be ranked by magnitude, and knowledge gaps can be identified for each risk. Once the knowledge gaps are understood and sequenced by priority, innovation ideas can be formulated and tested with prototypes for their feasibility in closing the gap.

 

In conclusion

The only certain thing in this Covid-19 vaccine manufacturing landscape is that there is a low degree of confidence about what will really happen in the coming years with regard to capacity and sources of supply. Given this uncertainty, it will be essential for large pharmaceutical organizations to work to improve transparency, focus and collaboration across their end-to-end value streams, while designing in the flexibility to change and adapt quickly to meet changing conditions. These are all critical aspects of lean thinking and practice.