In-depth: Promising signs for local biopharmaceutical production

In-depth: Promising signs for local biopharmaceutical productionPHOTO: WHO
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From brand new medicines for cancer and rheumatoid arthritis, to some COVID-19 vaccines and experimental HIV treatments, so-called biopharmaceuticals have taken the pharmaceutical industry by storm in recent decades.

One snag, however, is that biopharmaceuticals are typically much more expensive than traditional pharmaceuticals. Figuring out ways in which to manufacture and market biopharmaceuticals more cheaply should thus, arguably, be a high priority, particularly in middle-income countries like South Africa where high prices can limit access.

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The good news is that local research aimed at doing just this is already underway. There are also promising signs on local production of biopharmaceuticals, but progress will be difficult without greater investment.

What are biopharmaceuticals?

Biopharmaceuticals are therapeutic drugs, vaccines, and diagnostics in which the active ingredient (API) – the component of the drug or vaccine that makes it effective in combating an illness – is produced in a living substance. The living substance acts as a ‘miniature factory’ in which the active ingredient is grown and replicated.

Living substances in which biopharmaceuticals are produced include micro-organisms such as bacteria and yeast and living cell lines including mammalian, insect, plant, and even human cell lines.

The micro-organism or cell line most suitable for producing different biopharmaceutical drugs depends on the complexity of the active ingredient being manufactured, among other factors. Chinese Hamster Ovary (CHO) cell lines, a type of mammalian system, are used to produce more than half of biologic medicines on the market today.

Biologic drugs (also known as protein therapeutics) are a relatively new class of drugs, with the first product introduced in the 1980s to treat diabetes. However, the development of new biologics is now outpacing that of traditional small molecule medicines along with the importance of this class of drugs to both public and individual health. The introduction of protein therapeutics has already provided important new treatment options and advances in a range of areas – including cancers, infectious diseases, diabetes, and auto-immune diseases.

For the past few months, I have been injecting myself once/wee with Adilimumab (Humira), an anti-TNF agent.
PHOTO: Justin R/Flickr

Protein therapeutics include monoclonal antibodies, such as the cancer treatment trastuzumab (Herceptin) and rheumatoid arthritis treatment adalimumab (Humira) – both of which remain largely inaccessible in developing countries due to high prices.

Protein therapeutics also include a new class of experimental HIV treatments called broadly neutralising antibodies (BnAbs).  (Spotlight recently reported on promising bNab study findings here.)

Protein-based vaccines which, like protein therapeutics, are manufactured in bioreactors of micro-organisms or cell lines, also include a range of important products needed for public health, including vaccines against hepatitis B and the human papilloma virus. More recently, Novavax introduced a protein-based vaccine against COVID-19, which is propagated in moth cell lines, while multiple other protein-based vaccines for COVID-19 are in the pipeline.

Can South Africa produce protein therapeutics or protein-based vaccines?

Currently, South Africa has no capacity to produce protein therapeutics or protein-based vaccines at a commercial scale – the scale required to provide health products in the public sector or market them in the private sector. Partially state-owned Biovac and local pharmaceutical company Aspen’s manufacturing capacity in this space is presently limited to formulating, filling, and finishing vaccine vials with active ingredients imported from overseas. (Spotlight previously reported on Biovac and local vaccine production capacity here.)

However, in an important advance for local vaccine API production capacity, Biovac announced recently that it had secured a technology transfer arrangement with the US-based company ImmunityBio to manufacture the company’s viral vector COVID-19 vaccine locally. It should be pointed out though that the processes for manufacturing new generation vaccines (such as viral vector and mRNA vaccines), are in many ways distinct from those used to manufacture older, conventional vaccines (such as protein-based and inactivated virus vaccines).

As Biovac CEO, Dr Morena Makhoana, tells Spotlight, the requirements and design of the manufacturing facility for vaccine production differ depending on the type of vaccine produced.

Can South Africa produce clinical trial batches of biologics?

Some academic research groups in South Africa have the capacity to produce protein therapeutics and protein-based vaccines at a lab level. This capacity includes the discovery and development of new therapeutic and vaccine candidates. Academics and research groups at the University of Cape Town (UCT), for example, have produced new vaccine candidates against HIV and human papilloma virus, among other diseases.

PHOTO: Sanofi Pasteur/Patrick Boulen

Yet, despite academic-level capacity to develop new candidate products, no company in the country has the capacity to manufacture therapeutic proteins or protein-based vaccines at the scale needed for clinical trials.

Dr Tsepo Tsekoa, Research Group Leader of Biomanufacturing Technology Demonstration at the Council for Scientific and Industrial Research (CSIR), explains: “Currently, when we need to make clinical grade batches of therapeutic or vaccine candidates, and we have done this before, we have to go offshore and at great cost recruit companies to manufacture candidate products.”

CSIR steps into the breach

The fact that we cannot produce adequate capacity of protein therapeutics and vaccines for clinical trials is holding back research, development, and commercialisation of new and bio-similar (generic) products in the country.

To address this gap, the CSIR is seeking to develop a new manufacturing facility on its Pretoria campus that can produce clinical trial size stock of biologics. The CSIR aims to establish a cGMP facility able to produce biopharmaceuticals using a range of different manufacturing approaches (also called expression systems).

cGMP refers to the “Current Good Manufacturing Processes” standards that companies must meet to manufacture, register, and sell therapeutic drugs and vaccines in South Africa.

Dr Santosh Ramchuran, Research Group Leader of Bioprocess Technology Development at CSIR, adds: “We are in very early stages of planning and securing and raising funds for the facility. It takes a lot of funds to fund these facilities. So far, we have secured partial funding and we will be breaking ground this year, but in reality we should only be fully operational in three years’ time as a cGMP facility that can manufacture clinical trial batches.”

Deputy President Cyril Ramaphosa delivers a keynote address at the 5th CSIR conference, themed 70 years of Ideas that work, held at CSIR International Convention Centre, Pretoria, 08/10/2015. Siyasanga Mbambani

The Department of Science and Innovation did not respond to a request from Spotlight for clarification on how the facility at the CSIR would differ from, or complement, a proposed BRICS vaccine research and development center. During the 10th BRICS Summit, held in Johannesburg in 2018, BRICS heads of states committed to establishing a vaccine research centre in South Africa. President Cyril Ramaphosa has subsequently urged its establishment, but a timeline for its creation remains unclear.

The cost of building a biopharmaceutical manufacturing facility in South Africa

Key barriers to establishing commercial-scale manufacturing capacity in the country include the high price tag associated with constructing a manufacturing facility and the lack of funders willing to shoulder the high costs and associated risks.

Constructing a “fully fledged biological facility that has end-to-end capability” costs 200m euros [over R3 billion], says Biovac’s Makhoana.

“One can start small. The minimum that we think we will need is 100m euros,” he adds, referring to the financial requirements of constructing a facility able to produce ImmunityBio’s vaccine. “We are lining up funders and at the right time we will make those known.”

Professor Ed Rybicki, Director of UCT’s Biopharming Research Unit, says that constructing a facility able to produce APIs for human vaccines at a commercial scale costs over R1 billion and can go much higher depending on the size of the facility. He notes, however, that constructing a facility to develop therapeutics and vaccines using plants is far more affordable than developing a facility for CHO cell line production and can start at around a half a billion rand.

Can new, more affordable manufacturing approaches enable localisation?

To enable local manufacturing and to bring down the cost of producing biopharmaceuticals, research groups in the country are looking for ways to reduce the cost of setting up facilities and manufacturing biologics.

One approach that has been championed by researchers at UCT’s Biopharming Research Unit (BRU) is the use of plant cell lines to manufacture biologic products. Tamlyn Shaw, co-founder of Cape Bio Pharms, a spin-off of BRU, explains: “The plant-based platform has been around for nearly 30 years now, but they only recently started to really take off when the transient expression system began to develop,” making plants more effective producers of proteins.

The BRU has developed processes to manufacture a variety of protein therapeutics and protein-based vaccines in plants. Yet, as the manufacturing capacity does not exist to produce these products locally, it has only been able to license this knowledge to companies producing plant-based biologics overseas.

The CSIR is also developing techniques to manufacture pharmaceutical products in plants and is currently developing processes for manufacturing BnAbs for HIV, as well as a monoclonal antibody for rabies in plant cell lines.

Meanwhile, the Stellenbosch-based biopharmaceutical company, AzarGen Biotechnologies, is developing a plant-made biosimilar (generic version of biologic drugs) of rituximab, an important treatment for several cancers, with support from the US-based company iBio. The plant-made therapeutic candidate is currently undergoing pre-clinical tests in the United States.

And that’s not all.

Professor Natalya Nikitina and her colleagues at the University of Witwatersrand are trying to redesign and improve egg albumin (egg white) expression approaches to increase protein yields and remove allergens, as an alternative approach for affordable production of biologics.

From diagnostics to biopharmaceuticals

A handful of biotech companies in the country – including the UCT spin-off Cape Bio Pharms and the CSIR spin-off CapeBio – are producing proteins for use in medical diagnostics, including for diagnosing COVID-19.

Shortages of diagnostic proteins (reagents) experienced during the COVID-19 pandemic have contributed to testing delays in many countries, including South Africa. Cape Bio Pharms is currently producing proteins that are being used both in locally and internationally manufactured antibody test kits for COVID-19. CapeBio has developed a PCR test kit together with CSIR using locally produced enzymes (a type of protein able to catalyse biological reactions).

Shaw explains that the proteins used in the diagnostics “are almost the exact same as those used in therapeutics and vaccines, it is just that the regulatory requirements are a lot more stringent as you work your way up”.

PHOTO: Matt Allworth

Daniel Ndima, CEO of CapeBio, explains that facilities manufacturing enzymes to go into diagnostic kits must have ISO 13485 certification, whereas facilities making proteins for therapeutics and vaccines which are put into people must have various accreditations including cGMP certification. (Spotlight recently reported on the regulatory requirements for medical devices manufacturers, including ISO 13485 here.)

As noted above, constructing a facility that meets cGMP standards and is large enough to produce therapeutic drugs and vaccines at commercial scale typically costs over a billion rand.

Ndima notes that the capacity developed in the country to manufacture reagents “is a stepping-stone towards local manufacturing of biopharmaceuticals”. He adds that we are “in a space where if we have the right partners and available capital, we would be able to step up and start research and development of some novel therapeutics in-house, working together with other local partners operating in this space”.

How to fund a new manufacturing facility

Companies seeking to establish manufacturing capacity and introduce new affordable manufacturing processes, such as plant-based manufacturing processes, must overcome the reticence of investors to invest not only in Africa but also in new manufacturing approaches.

The challenges faced by African companies in securing funding to localise pharmaceutical manufacturing are well known. During a February 2021 roundtable discussion hosted by Knowledge Ecology International on “Pathways to Scale-Up Manufacturing Capacity for COVID-19”, Fred Abbott, Professor of International Law at Florida State University, explained that “none of the big multilateral agencies…, the Foundations…, or the sovereign wealth funds, or the classical asset managers have been financing the construction of vaccine production facilities in Africa”. He contrasted that with the developed world where there is “a tremendous amount of subsidization going into the construction of new facilities”.

A further challenge is the lack of investment by traditional pharmaceutical companies into ‘disruptive’ technologies like plant-based manufacturing approaches.

Nikitina says that “conventional pharma companies are already invested in the CHO production facilities, which cost a lot of money to build. If there are alternative ways to produce these things cheaper, why on earth would they want to invest in them if they have already gone down the road of investing in CHO systems?” Rybicki concurs: “It is sunk cost. If you have sunk a couple hundred million dollars into a big CHO plant that makes monoclonal antibodies, why would you switch to plants?”

Mauritz Venter, co-founder and CEO of the Stellenbosch-based biotech company, AzarGen, adds that the low number of plant-based biologics that have entered the market to date adds to the perception that investing in the technology is high-risk, particularly in developing countries. Venter says that AzarGen hopes to change that perception.

A future of plant-based biotherapeutics and vaccines?

Less than a handful of therapeutic proteins and protein-based vaccines produced in plant cell lines have been authorised by stringent regulatory authorities to date. However, there are important signals that countries with mature regulatory agencies are embracing plant-based approaches for manufacturing drugs and vaccines and that these products will become more common in coming years.

The first plant-based biologic therapeutic approved in the United States in 2009 is Pfizer and Protalix’s Elelyso – a treatment for Gaucher disease produced in carrot cells. The U.S. Food and Drug Administration granted Emergency Use Authorisation for Zmapp in 2015 – a treatment for Ebola produced in tobacco plants.

PHOTO: Marco Verch/Flickr

Many other protein therapeutics and protein-based vaccines are in various stages of development by companies such as Kentucky Bioprocessing and iBio in the United States, Medicago in Canada, and South Africa’s BRU and CSIR, among others.

Medicago has, for example, conducted phase 3 trials of its plant-based seasonal influenza vaccine, which is under regulatory review by Health Canada. And, in October 2020, Medicago announced that it had received $173 million from the Canadian government for research, development and manufacturing of its plant-based COVID-19 vaccine.

CSIR’s Tsekoa notes that while regulatory pathways were formerly perceived as a large barrier to the introduction of plant-based biologics, regulatory guidelines are now catching up and the European Medicines Agency, for example, “has detailed guidelines around how you would prepare dossiers and how you would actually develop processes under cGMP for plant-based production”.

Large loan shifts local ecosystem

While local companies in Africa have long struggled to secure financing for manufacturing facilities, in a potentially game changing development for the continent, Cape Bio Pharms announced in December 2020 that it had secured a loan of R900 million from the European Investment Bank (EIB) to construct a facility to produce plant-based therapeutics and vaccines in Mauritius.

The facility will be named Cape Biologix and will be a subsidiary of Cape Bio Pharms. The envisioned Mauritius-based facility will be the only one in Africa able to produce both protein therapeutics and protein-based vaccines at commercial scale.

The loan builds on investments by the Foundation for Innovative Diagnostics (FIND) in Cape Bio Pharms towards the expansion of its pilot plant in Cape Town to produce plant-based diagnostic reagents on a large scale.

Shaw explains that “the Mauritius facility will focus on producing vaccines and therapeutic proteins, but that it is a long-term project and we have to first meet certain milestones at Cape Bio Pharms in order to unlock the EIB funding… We first have to get Cape Bio Pharms sustainable, stable and growing”.

Shaw says that Cape Bio Pharms initially sought to secure funding to construct a facility in South Africa, but that South Africa was not eligible to receive the loan secured by Cape Bio Pharms from EIB.

The Department of Science and Innovation did not respond to requests for comment on the challenges faced by South African companies in securing financing for localisation of manufacturing capacity and the role that government can play in addressing this financing gap.

More money needed

While the EIB loan to Cape Bio Pharms is a critical step in the right direction, financing remains necessary to localise manufacturing capacity, including plant-based production processes in South Africa. Biovac will also need to secure large financing commitments to build a facility able to produce the viral vector vaccine for which it has secured a technology transfer arrangement with ImmunityBio.

Additional financing will also be required if the continent wants to produce other new generation vaccines – such as mRNA vaccines, which are more affordable to produce but have more complex handling and distribution requirements.

Further, while plant-based manufacturing approaches promise to reduce construction and manufacturing costs, plant-based expression systems will not be suitable for production of all therapeutic proteins and protein-based vaccines, and investment in other manufacturing platforms remains necessary.

“Plants are great for making antibodies and other more complex proteins, but there is definitely still a need for other manufacturing systems,” Shaw explains. “There is just a need for local capacity building in every sphere.”

Venter adds: “There is a building awareness of a few companies in South Africa being part of the biotech revolution. There are lots of exciting developments and movements. Hopefully, this momentum will attract a new breed of local investors with a larger risk appetite.”