Pharma industry insiders view vaccines as one of the most challenging products to manufacture, fundamentally due to the inherent biological variability of the pathogen itself, which is the starting block of any vaccine, as well as the resulting inherent variability of the biological raw materials and processes required in vaccine production. For this reason, the product is very much the process when it comes to vaccine manufacturing. This has also been attributed as one of the main reasons for the relative scarcity of vaccine players globally.
Conventional vaccine manufacturing proccess
|Step 1||Step 2||Step 3|
|Pathogen antigen produced||Viral particles collected and further processed as necessary||Vaccine is formulated by adding adjuvants, stabilizers and preservatives as necessary|
The lead time to produce a vaccine lot ranges from several months (e.g., influenza vaccine) to three years (e.g., pentavalent and hexavalent combination vaccines).
It is also estimated that manufacturing facilities can cost between USD 50 to 500 million per antigen, and as much as USD 700 million for multiple vaccines. In 2020, GSK announced a USD 100 million expansion of its Montana manufacturing site in the US to meet increased demand for Shingrix, its shingles vaccine. In 2019, MSD (Merck & Co. in the US) announced a USD 650 million investment in a new US production facility in North Carolina for its Gardasil vaccine.
There are currently two main types of vaccine manufacturing platforms.
The traditional manufacturing process – in use for over 60 years now – is known as ‘egg-based vaccine production’, which, as its name indicates, uses fertilized chicken eggs. The entire process takes approximately six months. However, a number of challenges associated with this manufacturing platform – the vast number of pathogen-free eggs required, the challenge of growing some virus strains in hen eggs, and others – has led to the development of cell-culture vaccine production technology.
Cell-culture vaccine manufacturing technology isolates and grows viruses in so-called Madin-Darby Canine Kidney (MDCK) cells rather than fertilized eggs. These MDCK cells can be frozen in large quantities and are able to grow viruses closer to the current strains circulating in the public. The principal drawback for this approach, however, is the high-cost of the fermentation plants needed to grow cell-culture vaccines.
Taiwan vaccine developer Medigen is a proponent of cell culture production. Vice-chairman & CEO Dr. Charles Chen explains, “egg-based vaccine production has a number of challenges. For example, during an avian virus pandemic, the egg supply may be limited. In contrast. a cell bank will ensure a stable supply of key biomaterial components. Furthermore, as our cell culture technology platforms use serum-free media and employs a ‘single use’ closed manufacturing system, we have no risk of contaminants like Bovine Spongiform Encephalopathy. Cell-based production is also rapidly expandable and scalable, and cell culture is usable for many different types of vaccines such as seasonal flu vaccines, dengue and HFMD.
More innovative manufacturing platforms are continuously being developed. For instance, some investigators and companies are exploring using plants to produce vaccines in a process that can be as short as only five to six weeks. Some of them are even edible vaccines, which could provide an easier and more convenient route of administration versus injections. However, to date, no plant-based vaccine has been approved by any major regulator, though Canadian player Medicago is developing a plant-derived Virus-Like Particle (VLP) vaccine candidate for COVID-19, in conjunction with the pandemic adjuvant from vaccine giant GSK, which entered Phase 2/3 clinical trials in December 2020.
Supply vs demand
With the negative reputation of the vaccine industry as being a relatively low-profit one, a recurring challenge is ensuring that productioná meets demand, especially when it comes to fluctuating demand as well as demand in less economically-developed markets. For instance, in January 2021, the International Coordinating Group (ICG) on Vaccine Provision, which includes the WHO and UNICEF, and is financially supported by GAVI, announced that it would establish a global Ebola vaccine stockpile to prepare for future outbreaks. The Ebola vaccine in question is the one manufactured by MSD (Merck & Co. in the US and Canada) but supply bottlenecks have led to delays, with stakeholders expecting it to take up to three years to meet the stockpile target of 500,000 doses (which would include other Ebola vaccines as they become available). The WHO has explained that the situation is particularly difficult for Ebola vaccines because Ebola outbreaks are relatively rare and unpredictable, so there is no natural market for the vaccine.
The Research Council of Norway CEO Dr. John-Arne Røttingen shares his experience leading the MSD Ebola vaccine trial in Guinea, which eventually led to WHO’s development of an R&D blueprint mechanism as well as a new global organization able to independently finance and develop vaccines for epidemics – now known as the Coalition for Epidemic Preparedness Innovations (CEPI). As Dr. Røttingen puts it, “[it is fundamental] to strike a balance between the incentives offered to innovators on the one hand, the interests of payers and healthcare systems on the other, and ensuring access to health technologies across countries of different purchasing power. You need to incentivize innovation to have any access at all, because you need the technology first, but then there is also a need for different policies to ensure equitable access.”
You need to incentivize innovation to have any access at all, because you need the technology first, but then there is also a need for different policies to ensure equitable access.
John-Arne Røttingen, The Research Council of Norway
As with any healthcare product, the journey does not end with the regulator’s approval. After all the R&D and manufacturing phases have been completed, the final task remains: ensuring the product reaches the patient or the consumer.
As Deloitte US Life Sciences Supply Chain Practice Managing Director Joe Lewis summarizes, “the real issue is not actually delivering the product into the market, it is ensuring that individuals are successfully vaccinated … I think about this in terms of a ‘distributability index’: the more distributable a product is, the more people that product can reach.”
Certainly, the product characteristics affect its distribution requirements. In the case of COVID-19 vaccines, different vaccine candidates had different cold chain storage and transport requirements, which would affect their so-called ‘distributability index’. Lewis hypothesizes, “assuming that we have a number of approved vaccines with similar efficacy, I think it is reasonable that products with a lower distributability index could still be deployed within populations that are easier to reach, such as frontline healthcare workers. It is all about looking at the available vaccine options and then assessing the optimal portfolio and distribution of products based on the needs and characteristics of the population groups that need to be vaccinated that would ultimately improve community health outcomes.”
DHL Life Sciences and Healthcare president Larry St Onge summarizes, “the environment is still very fluid since we are still waiting to ascertain which vaccines are going to arrive when, so at DHL, we are still in an assessment period. Obviously, Pfizer’s vaccine has started to receive Emergency Use Authorization (EUA) in various countries but there are also many other opportunities within the pipeline. This is critical since Pfizer cannot supply the only solution globally, it will take multiple vaccine manufacturers to resolve the global pandemic.”
He also emphasized the importance of public-private partnerships within the supply chain sector. “What is absolutely imperative for all of us is the need to build a collaborative public-private framework that can drive a focus on the creation of a more resilient supply chain globally. We see an important opportunity for the private sector to be of value to the public sector here. Governments have found themselves quite challenged and stretched at various moments during the pandemic, and this is a result of them lacking the ‘intellectual sweat equity’, as I would call it, when it comes to understanding and dealing with the stringent requirements and standards of the life sciences and healthcare industries. We are talking about critical aspects like Good Distribution Practice, Good Manufacturing Practice, compliance, and so on, that are incredibly complex.”
UNICEF Supply Division director Etleva Kadilli, who leads the supply chain operations of the world’s largest single buyer of vaccines, concurs, “we work with partners in the private sector to strengthen the supply chains of the governments for whom we work. This is very important since in many cases, the governments are the ones that ultimately distribute the supplies we procure to the people who need them.”
Another challenge, she highlights, is “the presence of counterfeit products, which is especially dangerous when it comes to medicines and personal protective equipment (PPE),” adding, however, that “it is reassuring that we have seen that our existing due diligence processes have proven strong enough to address situations like this in order to prevent sub-quality products from entering our supply chains at this critical time.”
While supply chain has historically been dismissed as another cost item to be minimized, in 2020, the global COVID-19 pandemic underscored the critical importance of the right investments within this space. As DHL’s St Onge expresses, “ultimately, it is a patient at the end of every delivery we make in this sector. Healthcare is absolutely the most important thing we help to provide, and the underlying imperative that I strongly believe everyone – from a DHL company perspective to manufacturers to healthcare providers to patients – needs to understand is the fact that, healthcare works best when the logistics do too.”