Vinod Kumar

PharmaCentral.com Guest Writers

Amid calls for developed nations to do more, US President Joe Biden recently announced that his administration will be availing 500 million doses of the BioNTech-Pfizer COVID-19 vaccine to 92 developing nations. The announcement was much welcome news, coming at a time when many low income countries are in a grip of rising coronavirus infections.

Low income countries are especially vulnerable to the pandemic due to, among other factors, their underdeveloped health systems and lack of local vaccine manufacturing capacity. If you consider that as of June 2021, of the 2 billion COVID-19 vaccine doses administered, only 0.3% has reached low-income countries, principally in Africa, where vaccination rates are as low as 1%. At this rate, it will take several years to achieve vaccine coverage that’s similar to that of wealthier countries.

So as much as Biden’s announcement is much welcomed, plenty of people are calling for a more sustainable solution. An official as COVAX, a UN scheme distributing jabs to poor countries, was recently quoted in the main press questioning whether the US pledge will have any impact at all. What is needed is expansion of vaccine manufacturing capabilities regionally, in Africa, Asia and Latin America, to produce generic vaccines quickly to avert needless deaths.

Problem is vaccine manufacturing is complex, and may not necessarily be cost-effective. It requires huge resources, expertise and time. In Africa, for instance, only Senegal is WHO prequalified to make vaccines. So for most of the continent, the option to repurpose existing facilities for local production does not exist.

The question on many peoples’ minds then is, what option do low income countries have? Is local vaccine manufacturing viable? Admittedly, this is vast topic and my is to provide an overview rather than a deep dive analysis.

What it takes to manufacture vaccines

In short, a lot! First, here are the headline figures: estimates very but generally between US$ 200 M to 700 M to develop a vaccine from concept to market, and another USUS$D 50 M – 130 M to construct, equip and commission the manufacturing facility. Development time and facility construction take at least 3 years, plus a further 1 year lead time to get the vaccine to market after commissioning.

Conceptual vaccine development process (adapted from multiple sources, including Robinson, 2016)

Money aside and perhaps most important, many things must perfectly align. Robust and well defined methods and processes have to be developed, testing and monitoring regimes established, and above all, a company-wide commitment to comply with internal and external standards and regulations established. It is why vaccinologists say “the vaccine is the process” referring to the sum total of different steps that define success or failure.

So while not impossible (COVID-19 has taught us what science can achieve), it is no small feat, particularly for a country with no prior manufacturing experience.

Basics of vaccine manufacture

There is currently no standard vaccine manufacturing process. Processes differ by vaccine platform and at times, from manufacturer to manufacturer. However, for most vaccines, the process involves some sort of cell culture/fermentation, isolation and purification of active substances, formulation, fill-and-finish, and packaging. The entire process, from start to finish can take anywhere between 7 days to several months.

If we take a biological-based vaccine, we can categorise the different manufacturing processes into three main steps: in the first step (upstream), the cell culture is developed, standardised and induced to produce the active substance (e.g protein or virus). In the second step (downstream), the cell culture is harvested, purified and filtered to produce the pure active substance. In the last step (fill-and-finish), the active is formulated (excipients and stabilisers added) into a vaccine, filled into vials, inspected and packaged ready to ship to the clinic.

The process for the manufacture of mRNA vaccines is less complex because it is mainly synthetic. It starts with a plasmid DNA for the mRNA being produced via fermentation. Using an enzyme-catalysed in-vitro transcription process, the mRNA that codes for the spike protein is produced. The new mRNA is chemically modified (capping and stabilisation) to render it biologically active. It is purified and then formulated into lipid nanoparticles in a microfluidic process. Once formulated, it undergoes fill and finish, quality control and packaging in the same way as other vaccines.

What potential obstacles would a new manufacturer face?

Vaccines are not created equal, but you knew that already. The range and relative production complexity of several vaccine types is shown below. At one end is the live attenuated oral polio vaccine with significantly lower complexity and production costs while at the other end is the pneumococcal conjugate vaccine.

Vaccine types and comparative production complexity

Notwithstanding, there are common equipment or equipment types shared across platforms such as bio reactors, filtration and purification, filling and lyophilisation equipment, although the sequence of operations and the specific cycles for each product may vary. In most cases, each product has its own dedicated facility requirements as well as skillset.

Here below are some of the most important considerations:

1. Process development and maintenance

Introducing new or changes to facilities, manufacturing equipment, processes or raw materials triggers regulatory examination to confirm that processes are robust enough to ensure the vaccine is equivalent to the product produced in the original clinical or reference batches. Erecting a new facility and the accompanying processes will be a significant undertaking because the facility and processes define the product, but also all stakeholders have to have visibility into how the manufacturing process, quality control, specifications as well as all the support utilities will pan out at commercial scale quite early one.

2. Raw materials and consumables

Many of the raw materials and consumables used in vaccine manufacture are highly specialized in nature, with a few being produced by biological production methods. For these reasons, there are only so many suppliers available and the supply situation is subject to shortages or long lead times, not helped that we are currently in the middle of a pandemic and pressure on supplies is heightened. When materials are in short supply they tend to be expensive due to usual supply and demand dynamics. One option is to qualify multiple suppliers especially for critical materials, but this means extra work auditing suppliers and qualifying materials, which likely increases costs of goods.

3. Regulatory affairs and commercialization

Vaccine regulatory requirements and steps for obtaining marketing approval are well documented. They are also broadly similar across the world although the exact compliance requirements differ from country to country. Also, some vaccine products may be made only for specific countries based on their requirements, and for these, regulatory agencies may have their own flexibilities built into review and inspection regimes.

Whatever the local arrangements, manufacturers are expected to comply with all requirements applicable for the relevant regulatory agencies (including those the company wishes to sell its vaccine). These requirements include adherence to good manufacturing practices as well as routine monitoring of adverse event data, and annual reporting of specific manufacturing information (e.g., data trends, change management, stability review, CAPA, etc).

In addition, a manufacturing facility will be routinely subjected to external audits and inspections to assess compliance with GMP, facility maintenance, manufacturing and quality systems, and performance of the process. For the uninitiated, this is a lot to take.

If the new company wishes to sell their vaccine to highly lucrative WHO and UNICEF projects (essential for long-term business sustainability), then compliance with WHO’s Pre-Qualification (PQ) is mandatory. A PQ assessment process can take up to a year to complete excluding any additional required to respond to queries.

But even before a vaccine can be considered for PQ, the sponsoring regulatory agency must be first qualified as “functional” by WHO. WHO’s standards for “functionality” are immense and currently, there are only two African states with an national regulatory agency adjudged as “functional” for vaccines sponsoring purposes.

Manufacturing costs

The costs of manufacturing a vaccine are influenced by several factors. Here, I will focus on facilities, equipment, raw materials, process development and labour but clinical development and financing costs. Facilities and maintenance, raw materials, production, personnel and compliance comprise direct costs, while indirect costs include the creation and implementation of quality systems, operations planning, inventory and distribution, and sales, marketing and management. In the table below, we list some of the important costs and how they could be reduced.

Major vaccine production cost drivers and ways to reduce them

Facilities and equipment maintenance

Constructing and maintaining a vaccine manufacturing facility is a major cost for a vaccine manufacturer. A green-field, purpose-built vaccine manufacturing facility in North America can easily cost 50 – 750 M US$ per antigen, depending on the complexity of design, automation, segregation, utilities, and contamination controls. Based on current rates, GMP space cost from 6k US$/m²; while non-GMP space costs 3k US$/m². The cost of clean rooms and containment rooms is higher. It can take up to 7 years to design, build, validate, and commission a manufacturing facility. These estimates are for developed countries, so actual facilities cost may be lower in developing countries, although not by much since many materials and fixtures need to be imported and some key personnel hired from other countries as expatriates.

Process development

The focus here is on the steps used to develop and validate the manufacturing process leading to a licensed product. The key steps for process and analytical development and associated time frames during clinical development are outlined in the table below.

Key vaccine development stages and process/system expectations

Costs of process and analytical development, manufacturing, and documentation are highly dependent on vaccine type, technical complexity, disease target and regulatory body. Some independent analysists have calculated that the Chemistry, Manufacturing and Controls (CMC) development aspects for a vaccine range from 5 M US$ to 50 M US$ and require between 50 and 100 person-years in human resources. If a manufacturer from a developing country chooses to licence technology or partner with an established manufacturer, this can reduce costs and development time significantly.

Labour costs

Having a motivated, technically competent and committed workforce is a major requirement for any vaccine manufacturer, irrespective of where there are domiciled. Companies also need to be able to hire, train, and develop their workforce, a challenge even for highly experienced manufacturers.

For many reasons we don’t have time and space to go into, there is a shortage of personnel with the requisite skills and expertise needed by the vaccine industry. The deep scientific knowledge required to support such an endeavour takes years to acquire, so developing countries are at a disadvantage when it comes to establishing and sustaining local vaccine manufacturing capacity.

Countries such as China and India have large populations to draw from, not mentioning the huge financial resources, which have enabled them to build relatively sound technical and scientific foundations within a single generation. It is not an accident that these countries have also successfully managed to enter into vaccine manufacturing. Other developing countries are not as well endowed, so developing a knowledge base in tandem with a comprehensive training system within a short period of time is not as easy.

Finally, staffing for an average facility in low-income country will often include local and several expatriate employees in order to entrench and safeguard the relevant technical skills. Expatriate staff, by their nature, require higher total compensation, which increases overall labour costs.

What options are available to developing countries?

The good thing is that the pace of technology and innovation now mean that production costs need not be a showstopper even for smaller, resource-poor countries. With small-scale, modular or disposable technologies, high-density bioreactors, and innovations in fill-and-finish processing it is possible for new entrants to successfully venture into vaccine manufacturing.

For low income countries, the proven route is starting with fill and finish capacity, and then through a phased approach, step up the value chain to manufacture antigens as well. This approach allows reduction of upfront investment risk while building manufacturing know-how in a controllable way.

As we mentioned earlier, not all vaccines are created equal. This also applies to building vaccine capacity. Biological-based production technologies (such as those for recombinant-protein or viral-vector vaccines) have higher capital and operational costs compared with novel mRNA-based vaccines, which can be easily and quickly synthesized in a chemical reactor. Further, mRNA-based processes will soon become even more accessible through mobile “RNA printers” that are promised to further reduce footprint, labour and cost commitments.

To negate the high up-front costs of purpose-built facilities, we recommend using modular and prefabricated facilities, which constructed off-site and delivered to the site where they will be put into use manufacturing. Prefabs have been used for many years in small molecule pharmaceuticals and offer benefits of fast delivery and capacity flexibility. They are now available for vaccine manufacturing, with delivery times of three to six months instead of 5 – 7 years.

An example of prefab solution is the one Exyte and Univercells Technologies have co-developed and is available for vaccines. Known as NevoLine, this system uses continuous/semi-continuous process equipment with automation, and a small manufacturing footprint which can be housed inside the ExyCell cleanroom. The facilities can be commissioned fairly quickly, typically within 3 months.

Finally, it is no secret that labour productivity is a major limitation in low income countries, but more so in many African countries. For these countries, productivity can be boosted through pool human resources and technology transfer from across the value chain – including from equipment and raw material vendors, to universities and NGOs. For instance, organisations such as WHO and PATH have platform which provide working pilot plant production processes (including all the SOPs, documentation and training), allowing new entrants to establish a robust production system fairly quickly while managing to reduce development costs and improve productivity.

So there we have it. Vaccine manufacturing is a capital-intensive endeavour. Short and long-run product costs are primarily driven by development and production-related costs, with facility maintenance, compliance with regulations, raw materials and labour being the most significant contributors. Countries seeking to localize vaccine supply need to invest heavily in facilities, equipment, skilled labour and ongoing quality management with a long time-horizon.

But investment in facilities, equipment and skilled labour is not enough. Having sound scientific knowhow is critical to vaccine production, so the issue of methodical transfer of knowhow, the possession of which provides the basis for long-term viability of the venture, becomes especially important. In this sense, technology transfer is one of the main ways ventures in low income countries can possibly acquire vaccine manufacturing capacity.

References

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4. Gomez PL, Robinson JM, Rogalewicz JA. Vaccine Manufacturing. Vaccines, 6th ed. In: Plotkin S, Orenstien W, Offit P. Orlando, editors. WB Saunders Company; 2013. p. 44–57.
5. Wilson P, Giving developing countries the best shot: an overview of vaccine access and R&D; 2010.
6. WHO. WHO Prequalification Financing Model – Questions and Answers <http://www.who.int/medicines/news/prequal_finance_model_q-a/en/> [accessed 17.05.05].
7. WHO. WHO updates on regulatory system strengthening and prequalification activities; 2016. <https:///www.unicef.org/supply/files/RSS_and_PQ__updates_vaccines-ID_c_rodriguez.pdf> [accessed 17.02.07].
8. Sinclair A, Latham P. Vaccine production economics. In: Wen EP, Ellis R, Pujar NS, editors. Vaccine Manufacturing and Development; 2015. p. 415.
9. Plotkin S, Robinson JM, Cunningham G, Iqbal R, Larsen S. The complexity and cost of vaccine manufacturing – An overview. Vaccine. 2017;35(33):4064-4071. doi:10.1016/j.vaccine.2017.06.003

In this article, I compare excipients and formulation methods used in the four Covid-19 vaccines from Pfizer BioNTech, Moderna, Astra Zeneca and Janssen-Cilag (Johnson & Johnson), that have obtained emergency approval by the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) and its European counterpart, the European Medicines Agency, EMA.

Introduction

SARS Covid-19 has put vaccines into the public limelight again. Now more than before, we are all aware of the need for and challenges of timely distribution, as well as the importance of the cold chain. What is perhaps not clear to most people is that these challenges are heavily influenced by a vaccine’s inactive ingredients (excipients, solvents & adjuvants) as well as the platform.

In addition to stability, a vaccine’s formulation and excipients impact the economics of manufacture and the finished product’s presentation. It is the same way an engineer at Ferrari or Aston Martin designs an impressive V8 powertrain but finds that he or she still needs an equally impressive chassis for the new engine to deliver the performance.

This is why an understanding of how vaccines are formulated and the reasons behind choice of different excipients, from a pharmaceutical technology perspective, is equally important to appreciating differences in manufacturing, storage and distribution requirements.

First, I will briefly provide an outline of the vaccine platforms currently in use as this is important to formulation and excipients selection.

Vaccine Platforms

There are any number of ways to categorise vaccines. One method I like to use is classify them by the technology or platform used. Using this approach, we can distinguish four main platforms:

Whole pathogen vaccines

This is the oldest and most well-known method of vaccine development. It involves using an entire disease-causing organism in the vaccine to elicit the immune response, analogous to that obtained in regular infection. Whole pathogen vaccines are further divided into live attenuated and inactivated vaccines.

In live attenuated vaccines the disease-causing organism is weakened (attenuated) to curtail its disease-causing ability although it’s still able to replicate and trigger an immune response. An example is the Oral Polio Vaccine.

Inactivated vaccines have the genetic material destroyed – this way they are not able to replicate and infect cells, but are still able to trigger an immune response. Since inactivated vaccines do not always create a strong immune response as live attenuated vaccines, adjuvants (for example, aluminium hydroxide and aluminium phosphate are included in the formulation. An example is the Hepatitis A vaccine.

Subunit vaccines

These vaccines typically contain one or more immunogens from the surface of the pathogen. Antigens are usually produced through recombinant technologies. Subunit vaccines can be further divided into recombinant protein vaccines; toxoid vaccines, conjugate vaccines, virus-like particles and outer membrane vaccines.

The vast majority of vaccines in use today are subunit vaccines – they do not contain any whole bacteria or viruses and instead contain polysaccharides or proteins or their combination from the surface of bacteria or viruses, which are recognised by the immune system.

Agencies such as the World Health Organisation and the CDC, attest to the excellent safety profiles of subunit vaccines. Their only ‘downside’ is that they often require inclusion of adjuvants. Examples of subunit vaccines include

Nucleic acid vaccines

Nucleic acid vaccines work by providing genetic codes for host cells to produce antigens, which then stimulate the immune response. Nucleic acid vaccines can be further divided into RNA and DNA vaccines.

RNA vaccines use mRNA which is formulated in a lipid nanoparticle for protection and fusion with the cell membrane. A drawback of RNA vaccines is their inherent instability.

DNA, being more stable than mRNA, doesn’t require the same initial protection. DNA vaccines are typically administered using electroporation to allow cells to take up the DNA. There are currently no licenced DNA vaccines, however there are several in different stages of development.

Viral vectored vaccines

Viral vectored vaccines utilise harmless viruses to deliver the genetic code of target vaccine antigens to cells of the body, so that they can produce protein antigens to stimulate an immune response. Viral vectored vaccines can be developed quickly and on a large scale. They are also significantly cheaper to produce compared to nucleic acid or subunit vaccines.

Viral vectored vaccines can be further classified into replicating and non-replicating. In the former, viral vectors retain the ability to make new viral particles alongside delivering the vaccine antigen when used as a vaccine delivery platform. Non-replicating, as the name suggests, do not retain the ability to make new viral particles because some of the viral genes required for viral replication have been removed.

Differences by Vaccine Platform

The Pfizer BioNtech and Moderna vaccines are nucleic acid vaccines. Both the Pfizer BioNTech Covid-19 vaccine (BNT162b COVID-19 mRNA vaccine) and the Moderna Covid-19 vaccine (mRNA-12743 COVID-19 vaccine) are single stranded, 5’ capped messenger RNA produced by cell-free in vitro transcription from corresponding DNA templates that encode for SARS-Cov-2 spike protein.

Although mRNA vaccines are a relatively new technology (approx. 30 years old, compared to whole organism vaccines that were first introduced during the late 1700s), they are well studied. They also offer many advantages:

1. Firstly, no live components are involved, so there is no risk of the vaccine triggering disease.
2. The mRNA, due to its transient nature, also presents zero risk of becoming integrated with our own genetic material.
3. Moreover, the immune response involves both B and T cells.
4. Finally, and perhaps more importantly, they are relatively easy to manufacture.

The major downsides of mRNA vaccines are that they often require ultra-cold storage, and almost always require booster shots for maximum effectiveness. We will touch on this later in the article.

By comparison, the Jansen-Cilag and AstraZeneca vaccines are viral vectored vaccines, so they use a different approach to instruct human cells to make the SARS-2 spike protein. The Jansen-Cilag Covid-19 vaccine (COVID-19 vaccine (Ad26,COV2-S [recombinant])) uses a non-replicating adenovirus (a Novel Adenovirus Type 26) from their AdVac technology and grown in PER.C6 cell line.

The AstraZeneca Covid-19 vaccine (COVID-19 (ChAdOx1-S [recombinant]) also uses a non-replicating adenovirus, this one being a chimpanzee adenovirus (as opposed to Ad26, which is human adenovirus) known as Oxford1 (or ChAdOx1).

A schematic illustration of an adenovirus vector vaccine is shown below:

Fig. 1: Schematic illustration of an adenovirus vector vaccine

The adenoviruses used in these vaccines are engineered to only carry the genetic code for the SARS-2 spike protein. Upon entering human cells, they use that code to make spike proteins. These vaccines mimic natural infections, which is advantageous in triggering strong cellular immune responses as well the production of antibodies by B cells.

The technology is well-established, with two other vaccines already approved (Ebola & Zika vaccines). However, adenovirus vaccines are relatively complex to manufacture, and with time, their effectiveness reduces.

How Covid-19 Vaccines Differ in Formulation and Excipients Used

Pfizer BioNtech and Moderna Vaccines

The Pfizer BioNtech and Moderna vaccines are available as sterile, multi-dose colloidal dispersions for intramuscular injection. The mRNA in both vaccines is encapsulated in lipid nanoparticles (LNPs). LNPs are chosen to overcome the inherent hydrolytic instability, poor membrane permeability, and the abundance of RNAses in the body.

Lipid nanoparticles (sometimes called solid lipid nanoparticles, SLNs) are colloidal carriers made from lipids. As a drug delivery technology, LNPs emerged in the early 1990s as an alternative to traditional emulsions and liposomes. Although their exact structure is still under debate, LNPs are generally thought to consist of a solid lipid core (unlike liposomes which have an aqueous core) and an external phospholipid layer (membrane). A schematic illustration of an LNP is shown in figure 2. You can also watch an excellent YouTube on LNPs through this link.

Fig. 2: Schematic illustration of an lipid nanoparticle vaccine

For the Pfizer BioNtech and Moderna vaccines, LNPs are obtained by admixing mRNA, various lipids, which include a neutral phospholipid, cholesterol, a polyethylene-glycol (PEG)-lipid, and an ionizable cationic lipid (which has amine groups (at low pH) and facilitates interaction with the anionic mRNA during particle formation and also membrane fusion during internalization). The PEG-lipid controls particle size and acts as a steric barrier, preventing aggregation during storage. When complexed with the mRNA, the LNPs-mRNA particles have sizes in the range of 60–100 nm.

Table 1 below summarises the main differences in Pfizer BioNtech and Moderna vaccines’ formulation and excipients:

Table 1: Formulation of Pfizer BioNtech and Moderna COVID-19 vaccines

LNPs are particularly unstable thermodynamically. In addition, they are susceptible to chemical instability, which can arise from hydrolysis and oxidation of the lipids in the LNPs, as well as oxidation of unsaturated fatty acid groups. This makes LNPs systems especially susceptible to storage conditions, which helps explain, in part, to the stringent handling conditions required of mRNA vaccines.

Janssen-Cilag (Ad26. COV2.S) and AstraZeneca (Vaxzevria or AZD1222)

Janssen-Cilag (Ad26. COV2.S) and AstraZeneca (Vaxzevria) vaccines are available as sterile, multi-dose aqueous suspensions for intramuscular administration. Liquid suspensions are an efficient and the go-to format for viral vector gene delivery systems. However, the challenge faced by formulators is ensuring long term stability since, unlike conventional pharmaceutical products, they are complex biological structures susceptible to chemical and physical stressors, such as changes in solution pH, ionic strength, redox potential and surface activity.

Thus, the aim of formulation efforts here is to prevent conditions likely to trigger degradation pathways, such as denaturation of the capsid protein and nucleotides, aggregation, hydrolysis and precipitation and adsorption of the vaccine onto the container walls. This mandates the use of buffers as well as functional excipients and other materials in the formulation, such tonicity agents and stabilisers, non-ionic surfactants to prevent adsorption to glass surfaces and cryoprotectants (sucrose, ethanol or cyclodextrins), free-radical oxidation inhibitors and metal chelators (edetate).

Table 2 below summarises the main differences between Janssen-Cilag and AstraZeneca Covid-19 vaccines’ formulation and excipients:

Table 2. Formulation and Excipients used in Janssen-Cilag (Ad26. COV2.S) and AstraZeneca (AZD1222) COVID-19 vaccines

Differences in Storage Requirements

All vaccines (with the exception of a select few) require high quality and robust cold chains to guarantee stability and viability. These conditions are not arbitrary – they are arrived at from extensive stability studies and conditions where the viability of the products is monitored.

As hinted to previously, the mRNA vaccines are especially vulnerable to handling conditions, hence their requirements are particularly elaborate compared with adenovirus vaccines.

Of the two mRNA vaccines, Pfizer’s is the more challenging to handle, requiring shipping and storage in ultra-cold freezers. I was not able to find any studies on storage stability in the public domain on mRNA COVID-19 vaccines, however Onpattro® , a marketed LNP product has a shelf-life of 36 months when stored between 2° and 8 °C. It is possible that in future, these conditions will be updated as more storage stability data emerge.

A summary of the key requirements for the different vaccines is below:

Pfizer BioNTech COVID-19 Vaccine

• 6 months maximum shelf life when stored in a freezer at -80°C to -60°C
• 31 days maximum shelf life at 2-8°C after thaw
• May be stored between 2 to 25°C for 2 hours prior to dilution after removal from the fridge
• Once diluted may be stored between 2 to 25°C for a further 6 hours
• Protect from room light and direct sunlight or UV light

Moderna COVID-19 Vaccine

• 7 months maximum shelf life when stored in a freezer at -25°C to -15°C
• 30 days maximum shelf life at 2 to 8°C after thaw
• May be stored between 8 to 25°C for up 12 hours prior to dilution after removal from the fridge
• Once punctured, the vial must be used within 6 hours
• Protect from room light and direct sunlight or UV light

AstraZeneca COVID-19 Vaccine

• 6 months maximum shelf life when is stored in a refrigerator between 2 to 8°C
• 6 hours maximum shelf life when stored between 2 to 25°C.
• Once punctured, the vial must be used within 6 hours
• Must not be frozen
• Protect from room light and direct sunlight or UV light

Vaccine Janssen-Cilag COVID-19

• 24 months maximum shelf life when is stored in a freezer between -25 and -15 °C
• 3 months maximum shelf life when stored between 2 to 8 °C after removal from freezer.
• Once punctured, the vial must be used within 6 hours
• Must not be frozen
• Protect from room light and direct sunlight or UV light

So there you have it. A summary of platforms for Covid-19 vaccines, the formulations and excipients used, and how these influence handling, storage and distribution requirements of Pfizer BioNTech, Moderna, Astra Zeneca and Janssen-Cilag (Johnson & Johnson)’s vaccines.

References

1. Schoenmaker, D. Witzigmann, J.A. Kulkarni, R. Verbeke, G. Kersten, W. Jiskoot, D.J.A. Crommelin, mRNA-lipid nanoparticle COVID-19 vaccines: Structure and stability, International Journal of Pharmaceutics, 601 (2021) 120586.
2. S. Rosa, D.M.F. Prazeres, A.M. Azevedo, M.P.C. Marques, mRNA vaccines manufacturing: Challenges and bottlenecks, Vaccine, 39 (2021) 2190-2200.
3. D’Amico, F. Fontana, R. Cheng, H.A. Santos, Development of vaccine formulations: past, present, and future, Drug Delivery and Translational Research, 11 (2021) 353-372.
4. Mäder, K. Solid lipid nanoparticles, Handbook of Materials for Nanomedicine, Jenny Stanford Publishing 2020, pp. 173-206.
5. Tatsis, N., Ertl, H.C., Adenoviruses as vaccine vectors, Molecular Therapy, 10 (2004) 616-629.

Earlier this year, Corporate Knights, a Toronto-based sustainability performance research and media company, released their Global 100 Most Sustainable Corporations rankings. The annual ranking is based on an assessment of more than 8 000 large global companies with revenues > US$ 1 billion. You can obtain more information via this link.

As one would have expected, renewable energy companies dominate, with Ørsted and Schneider Electric, bagging second and first spots this year. Pharmaceutical companies feature on the list, albeit at number 16 (Eisai), 65 (Sanofi), 71 (Takeda), 82 (AstraZeneca) and at 98 (Novo Nordisk).

The fact that pharmaceutical companies feature at all is something to welcome but at the same time the fact that so few pharmaceutical companies feature in the top 100 is disappointing.

Given how processes for the development, production, distribution and disposal of drug products use huge amount of natural, human and economic resources, a lack of interest in sustainability is potentially problematic and only helps further dents the sector’s image as well as its future sustainability.

With society increasingly placing high expectations on corporate entities, it is no longer enough to simply have good intentions, actions must follow words.

But first, what is sustainability?

Sustainability is one of those things that carry different meanings to different people. Sustainability experts say it is simply a business strategy that takes into account an organisation’s operations and their social, ecological and economic impact.

The consensus today is that sustainability is actually good business; a focus on sustainability boosts an organization’s top and bottom lines. This is why a recent survey of top executives at Fortune 500 firms revealed that they now consider sustainability a necessity for competitiveness and future survival.

Examining sustainability literature reveals three main pillars: the environmental, the social and, the economic— this is what is also referred to as profits, planet, and people. The idea here is that by actively addressing environmental and social issues companies can contribute to the society’s sustainability while also achieving their own long-term value (profitability, return on capital, etc).

The environmental pillar is what the majority of us are familiar with, thanks in part to Greta Thunberg . It is concerned with the reduction of carbon footprint, water usage, non-decomposable packaging, and wasteful processes, as part of a supply chain. Cleaning up these processes has been shown to be cost-effective, and financially beneficial while also positively impacting the environment at large.

The social pillar is about treating employees and the communities within which the business operates fairly and responsibly. Some of the important aims here include compassion and provision of responsive benefits, such as better maternity and paternity benefits, flexible working, staff development opportunities, etc.

And, finally, the economic pillar is about running businesses in an economically sustainable way; to be profitable and produce enough revenues long-term. It is not about making money at any cost, rather companies should aim to generate profit in accordance with other elements of sustainability.

Embracing these three pillars, namely social, environmental and economic sustainability is what economists refer to as the Triple Bottom Line.

There is currently no official universal measurement of sustainability in existence, and instead, organisations have developed industry-specific tools and practices to judge how social, environmental and economic principles function as part of a company.

Some success stories in Pharmaceuticals sector

AstraZeneca, Eisai, Biogen, Glaxo and Novo Nordisk are pharmaceutical companies that have both worked toward energy efficiency, waste reduction, and other ecological measures. They have also focused on social impact via partner initiatives in the areas of health and safety.

Across the industry as a whole, there is a major shift in thinking, with many companies imposing targets or starting initiatives aimed at reducing the impact of their activities and products on the environment.

Many are exploring ways to produce their products more efficiently and in a sustainable way; such as implementing ‘green’ IT practices designed to lower energy consumption; plastic neutrality and water sustainability.

But there’s still a lot to do

As mentioned earlier, the development, production, distribution, use and disposal of drug products has a major impact on environment. For instance, drugs taken by humans and animals find their way into rivers, lakes and even drinking water, and can devastate both aquatic ecosystems.

Sustainability needs to be a priority for any business operating in the sector. And increasingly, people of all walks of life are demanding for it. Very soon, companies will be called to account for all their operations, from carbon footprint, harmful emissions, water usage, etcetera.

The expectation today is that resources should be used responsibly, and where possible, reused to suit the global increase in population.

How do we move from here?

Obviously, there is no “one right solution” on sustainability. The best solution depends on the ambitions and stakes at each company.

Sustainability experts recommend a few useful actions outlined below:

1] Strategic commitment to sustainability: Corporate and business strategies need to be aligned with sustainability.

2] Compliance: There has to be a commitment to comply both with the spirit and letter of the law as it relates to waste management, pollution and energy efficiency.

3] Proactiv response: Rather than wait for a crisis, companies need to develop sustainability strategies today.

5] Transparency: Transparency is pre-condition for measuring and improving sustainability practices. Therefore, companies need to openly communicate with all key stakeholders, openly and truthfully, acknowledging their failures as well as their successes.

To conclude, sustainability remains a major challenge, a challenge that no single company can address. Although the pharmaceutical sector has a lot to do, it is encouraging to see a number of companies embrace sustainability policies. Sustainability is a megatrend that won’t be going away anytime soon.

An empathetic consideration of people’s lived experiences in new drug development is a key factor in availing products that improve patient outcomes while also reducing costs to society.

Enosh Mwesigwa PhD MBA

Pharmaceutical Industry Professional

The broad appeal and runaway success of the iPhone (and other products including the Fitbit Versa, Google Nest Learning thermostat, and Amazon’s Echo and Alexa devices) has been attributed to many factors, not least their elegant designs, library of applications and the genius of the engineers that created them. All these are valid points of view and I do not dispute them.

What is all the more interesting is that such personable products, such as the iPhone, Fitbit Versa and Nest Learning thermostat, should emerge out of tech. ‘Geeks’ after all are not your stereotypical touchy-feely types compared with, say, your regular healthcare professional.

Those who are interested in design will tell you that all the above-named devices were designed around the lived circumstances of customers. Engineers in tech call this pain points.

The iPhone is designed to address users’ pain points, mindful of the importance of simplifying users’ daily lives. It is not enough to solve a problem; the solution must also be easy to use, look and feel good, and provide a ‘good feeling’ while in use (not create new pain points).

Engineers put a lot of time studying pain points and mapping out the expectations of all their potential customers. Insights gained at this early stage feed directly into any solution they create.

Compare this with the pharmaceutical industry. Once a new drug substance has been identified and completed its clinical evaluation, product developers will embark on developing a dosage form – this is the embodiment of the drug substance that patients eventually use.

The choice of a dosage form is not necessarily guided by users circumstances in the way tech engineers do. Instead, it is the materials available, regulations and technology to fabricate the dosage form that guide selection.

Even in the build up to launching on the market, the drug product remains centre stage, with focus being placed on satisfying clinical needs, as defined by governments or physicians.

All along, end users (patients) remain a distant abstract. How their lived experiences fit in with the selected dosage form or route of administration or dosing frequency rarely feature in conversations.

If you are in doubt, consider this story:

Chester is a 3 year old boy. He was diagnosed with Minimal Change Nephrotic Syndrome just after his second birthday. His condition leads to leakage of protein into urine, which results into many health problems, such as low blood protein levels, high cholesterol levels, high triglyceride levels, and swelling. Nephrotic syndrome patients are also highly susceptible to infections. At various times, he has been prescribed a cocktail of medicines, including rituximab, prednisolone, tacrolimus, ramipril, amlodipine, hydrochlorothiazide, calcium-D, and atorvastatin, in addition to antibiotics which are administered to him from time to time.

For his tender age, Chester’s medication burden is unnecessarily high. His regimen is complex and only a selection of his medicines have approval for use in children of his age. Moreover, a good selection of these is only as tablets (which children of Chester’s age struggle to take).

The issues faced by Chester are not atypical. Patients with chronic diseases face similar challenges.

It is as though those who develop medicines somehow have a blind spot to the many challenges that children like Chester face. You can blame this state of affairs on the way healthcare has traditionally been structured; as patients, we have always depended on our physicians to recommend what to use, and for one reason or another, this has become the default approach.

But things do not need to be this way. As the tech sector has demonstrated, successful products are those developed from the perspectives of end-users. This is what tech calls empathy-driven product development.

Definition of Empathy

Simply defined, empathy is a person’s ability to recognize and share the experiences of another person, both intellectually and emotionally. It involves, first, seeing the other person’s situation from their perspective, and, second, sharing those experiences.

We can distinguish empathy at two levels: individual and organizational. At the individual level, empathy helps us respond appropriately in social situations, build social connections, and support and encourage others on an individual, person-to-person level.

At the organizational level, empathy is about a shared resolve within an organization to show empathy to all stakeholders, including a commitment to recognise and correctly respond to the needs of its customers.

Empathy is not the same as sympathy, a term that describes a feeling of care and concern. Sympathy does not involve a shared perspective or shared emotions.

Examples of Empathy in Products (Fitbit Versa Smart Watch)

Not very long ago fitness trackers were very basic pedometers. There was no option to directly estimate the number of calories burned. Then Fitbit released its range of smart devices (such as Fitbit Versa), which were personalised fitness trackers that also incorporated a smart watch and an app. This opened up new functionalities. Not only were these new devices pedometers, but they also were not able to track fitness, answer calls, send notifications, play music, track your pulse and sleep. Some devices had their own ecosystem of apps, which allowed further personalisation.

As one business analyst commented, smart watches are like “someone who knows more about what you need than you do.”

As I pointed out earlier, in tech, the product must not only be useful and meet a need, but it must also be easy to use, look and feel good and provide a good feeling while being used. Engineers describe these attributes in terms of usability and user experience (UX).

Elements of User Experience (Adapted from Nielsen Norman Group – Definition of user experience)

Now think of the last time you needed the use of any medication such as an inhaler (if you have a child who needs an inhaler device, you will know what I am talking about) or even the humble suppository.

While I hope the medicine was useful, it probably did not meet all the other parameters defined in user experience, such as ease of use.

I know I am pushing the envelope here and the Fitbit Versa and a suppository are literally worlds apart. However, the point is that many products out of healthcare rarely elicit pleasant experiences.

Many oral medicines are unacceptably bitter, medicine packages impossible to open without risking injury, instructions confusing, inhalers impossible to master, and as for suppositories, well, the less said the better! Basically, we’re expected to ‘swallow the bitter pill’ and get on with it.

A little empathy on the part of medicine developers would go a long way. It is not enough for a medicine to be safe and efficacious, patients’ lived experiences; namely their ages, circumstances, preferences, values, cultural traditions, comfort, emotional well-being and socioeconomic conditions, are of equal importance, and need to be included in the formulation equation.

Moving in the Right Direction

Fortunately, there is now a growing interest in using this empathetic approach to new product design within pharma.

Astellas Pharma, for example, is implementing what they call “Patient Focus Experience.” The company aims to understand what matters to the patient and integrating the insights garnered into their development programmes. This will without doubt close the gap between the patient’s needs and the company’s processes and products.

But we still have is that too many companies paying lip service to patients. They still see the world in this paternalistic, myopic way, and are failing to recognise that behind drug products are real people, who face `different pain points.

Opportunities to Apply Empathy

Pursuing empathy requires corporations, not just those that research and develop product in laboratories, to develop a nuanced understanding of patients’ lived circumstances. This is more than an intellectual exercise: it has to involve ‘walking the talk’, visiting and seeing at first-hand what patients go through; their day-to-day struggles and expectations.

Here are four consider of patients where more work is long overdue:

1. People with conditions which are chronic, symptomatic or affect activities of daily living

In conditions such as asthma, diabetes, arthritis, cardiovascular disease, COPD, chronic kidney disease, IBD and Parkinsonism, life for sufferers is a daily balancing act. From a pharmaceutical care perspective, people in this category face the following challenges of high medication burden and regimen, which often confuse patients about how and when to take medicine; regimen complexity; preventable side-effects and how to stay motivated and adhere to prescribed regiments. It has been estimated that these ‘pain points’ contribute up to 50% of patients on chronic medication regimens not adhere to their treatment, a staggering amount of waste!

2. People with conditions for which some aspects of disease are not fully captured in clinical trials

Drug bioavailability and disposition can be influenced by a number of disease conditions (such as diabetes, inflammatory bowel disease, pain, celiac disease, and other idiopathic and iatrogenic syndromes, often involving a broad range of or overlapping symptoms) as well as factors such as diet, age and ethnicity. These influences are easy to replicate during standardized clinical trials which are far removed from real-world circumstances under which patients are treated or live.

This calls for further research on how pharmacokinetic models and dosing recommendations can be best applied to patients with these conditions to ensure patient safety and product effectiveness.

Precision medicines designed to target specific genetic, molecular and cellular markers have the ability to provide patients with treatments that offer better outcomes compared with the current scatter gun approach that is in wide use.

3. Patients with conditions for which there are currently no therapies or few therapies or therapies that do not affect how the patient feels or functions.

This is a diverse group and as such the barriers experienced by different individuals are not uniform. However, consider individuals and children with neurodevelopmental disorders and disabilities, such as autistic spectrum disorders (ASD), as an example. In ASD there are often other overlapping symptoms and co-occurring disorders. Children also have a wide range of sensitivities – to colours, tastes, textures and noises, as well as physical and intellectual impairments. Many refuse to eat certain foods, let alone medicines, because of sensitivities to taste or texture. Parents of children with ASD know how difficult it is to convince them to swallow pills or teaching them how to use a complex device such as an inhaler. Clearly, more work needs to be done, ranging from ergonomics, to taste and palatability as well as simplifying regimens to address these challenges.

4. Conditions which selectively impact identifiable sub-populations, such as children and the elderly

Issues facing children are well articulated in the literature. However, there still remains a wide gap in the availability of medicines with specific approval for paediatric patients. In addition, many products are presented in formats that children are not able to or unwilling to take, and the younger the child, the worse the situation. This contributes to the wide use of unlicensed, off-label products, which increase the risk of harm.

Seniors, on the other hand, are one of the biggest but also the most heterogeneous users of medication. They have diverse health needs while also carrying a higher burden of chronic illness, frailty, mobility and manual dexterity issues, dysphagia, medication burden and regimen complexity.

What can be done? There are already proven and available technical solutions that can be deployed right away. These include:

• Simplifying medication regimens, including once a day dosing, prolonged/delayed release
• Use of combination products as well as package-drug systems
• Integrating human factors in device designs to improve usability (e.g asthma inhalers) and/or ergonomics
• Greater utilization of technologies such as tablet coatings and identifiable marking to improve identification and differentiation (why do all tablet have to look the same?)
• Increasing use of orally dissolving tablets (ODT) or fast dissolve systems, chewing gums and sublingual tablets in lieu of conventional (swallow) tablets.
• Efforts to use BIG Data and modern information technologies to capture insights from across the board and use these in product design
• More research into personalized and precision therapies to improve quality, safety and effectiveness

Conclusion

The current new product development processes are reminiscent of yesterday’s thinking. As the world around us rapidly transforms, and as patients become ever more sophisticated, informed and opinionated, product development professionals will need to start embracing empathy in the formulation equation. This empathetic shift will not only enable pharmaceutical companies to create truly impactful products in line with their existing goals but it will also reduce costs to.