Russia Pushes Ahead with Open License Approach to Sputnik V – Despite WHO Concerns Over Manufacturing Practices Analysis 02/07/2021 • Svĕt Lustig Vijay Share this:Click to share on Twitter (Opens in new window)Click to share on LinkedIn (Opens in new window)Click to share on Facebook (Opens in new window)Click to email this to a friend (Opens in new window)Click to print (Opens in new window) India’s Stelis Biopharma manufacturing site, where the Russian Sputnik V vaccine will be produced Despite the emergence of new WHO concerns over quality control at Sputnik V’s domestic production facilities, the Russian Direct Investment Fund (RDIF) is pushing ahead with a massive international “open-license” manufacturing effort for its Sputnik V vaccine – which breaks the traditional model of vaccine production and leverages existing capacity in poorer countries, desperate for doses. As such, RDIF has “broken the model of closed intellectual property” and adopted a vaccine scale-up model that is “fundamentally different” to most vaccine developers, Leena Menghaney, Global IP Advisor for MSF’s Access Campaign, told Health Policy Watch in an interview. But at the same time, a recent WHO review of manufacturing practices at one of the vaccine’s nine Russian plants identified a number of substandard manufacturing practices – illustrating how challenging quality control may be for the wider Russian model. The WHO review is not the only one to have found issues. Earlier this year, Brazil’s medicines regulator rejected Sputnik V’s request for approval, due to the contamination of some batches of the adenovirus vector, among other issues. Meanwhile, Slovakia’s regulator also has voiced concerns that the batches of Sputnik V it received did “not have the same characteristics and properties” as the version of Sputnik V reviewed in a Lancet study, which published favourable Phase III trial results for the vaccine earlier in February – with an efficacy of 91 % against symptomatic COVID-19 disease and 100% against severe COVID. And the European Medicines Agency (EMA) has delayed Sputnik V’s approval following the RDIF’s failure to submit additional clinical trial data by a deadline that was initially set for early June. At the same time, low- and middle-income countries, desperate for vaccines, have largely ignored such concerns. Since Russia’s own approval last August, almost seventy, mostly low- and middle-income countries have greenlighted the vaccine, which features a low price and easy storage requirements – and is even more attractive after India’s Serum Institute halted its AstraZeneca vaccine exports via the Global COVAX facility in March. Even more significantly, a number of countries, including India, Serbia, Argentina, and Iran, have already begun their own mass production of Sputnik V vaccines. That includes half a dozen manufacturers in India, which are set to produce 65%-70% of Sputnik V’s global supply, or about 850 million doses or more a year, according to RDIF projections. Should those aims indeed be reached, the RDIF and its partners could potentially produce nearly 10% of the world’s total vaccines for 2021. Non-Exclusive Deals With Multiple Manufacturers “The RDIF did what most vaccine developers and global health actors like the Bill and Melinda Gates Foundation should have done, which is to adopt a non-exclusive and open approach to vaccine manufacturing,” said Menghaney. Instead of sealing exclusive licenses with a handful of manufacturers, the RDIF has shared its vaccine technology and know-how with some 27 manufacturers, predominantly based in India or upper middle income countries, according to the Geneva Graduate Institute’s COVID Vaccine Manufacturing Tracker. That sets the RDIF apart from most other major pharma vaccine developers, which are primarily manufacturing, as well as distributing, vaccines in high-income countries – according to the Geneva Graduate Institute’s COVID Vaccine Manufacturing Tracker. Pfizer and Moderna, for instance, have signed a total of 6 and 9 agreements, respectively, with manufacturers. All are based in high-income countries like France, Switzerland, or Germany – except for one deal between Pfizer/BioNTech and China’s Shanghai Fosun Pharmaceutical Group. Even Johnson & Johnson, which recently struck an expanded manufacturing deal with Aspen Pharmacare in South Africa, is primarily producing vaccines in the US and Europe. And in the case of AstraZeneca, which has been the most aggressive in licensing production in low- or middle-income countries, including the Serum Institute of India, those licenses are exclusive. “The RDIF did not limit itself to one manufacturer,” added Menghaney. “If anyone wants [to produce] Sputnik V, they can go to RDIF and get it.” The RDIF has sealed deals with manufacturers from upper middle income countries, in contrast to the rest of Western vaccine developers, which are primarily manufacturing, as well as distributing vaccines in high-income countries Sharing Regulatory Dossiers within Countries Another aspect of RDIF’s approach, also evidenced in India, has involved the sharing of the same vaccine “regulatory dossier” with multiple manufacturers. In India, those companies include: Dr. Reddy’s; Panacea Biotech; Stelis Pharma (Strides arm); Hetero; Gland Pharma; Virchow; and the Serum Institute of India, said Menghaney. Sharing of dossiers is rarely done, due to trade secret and non-disclosure issues, Menghaney noted: “Instead of making manufacturers compete with each other, the RDIF encouraged them to produce the same common technical dossier and to work together to improve the yield of the vaccine.” The use of a common dossier not only hastened India’s regulatory approval of multiple new manufacturing facilities, but it has also allowed manufacturers to work together to optimise the yield of Sputnik V and to address quality control issues, such as contamination, which are common bottlenecks in the mass-production of adenovirus-based vaccines like Sputnik V. “The RDIF took a collaborative approach to manufacture the vaccine but also to scale it up,” said Menghaney, adding that no other company has adopted such a collaborative regulatory process for a COVID vaccine to date. She contrasts that with AstraZeneca, which signed about a dozen exclusive deals with manufacturers, including the Republic of Korea and the Serum Institute of India, effectively blocking other manufacturers in the same country from bidding to produce the vaccine. The problems around such exclusivity, became more evident last spring, when the Serum Institute of India halted its exports of the AstraZeneca “Covishield” vaccine to over 100 low-income countries in Africa and elsewhere participating in the WHO co-sponsored COVAX vaccine facility after Indian COVID cases began to skyrocket. That, in turn, set off a domino effect, stalling vaccine campaigns that had only just begun in LMICs around the world, and leaving them more dependent than ever on vaccine donations from rich countries, or alternatively vaccines from China or Russia. “The Serum Institute has an exclusive deal with AstraZeneca, and not just for India,” she said. “This probably means that these countries won’t be receiving any doses of the Oxford vaccine from other sources unless the agreement between AZ and SII is reviewed.” The RDIF’s approach, she said, is all the more welcome to access advocates against the backdrop of still limited vaccine sharing pledges to the global COVAX facility and continuing reluctance by the big mRNA pharma firms, like Pfizer and Moderna to freely share their vaccine know-how. RDIF Refuses To Reply On Manufacturing Quality Control Issues Despite that bright assessment, the preliminary WHO report, published last week, unearthed a number of concerning contamination issues at the Russian “Ufa Vitamin Plant” which manages the domestic Sputnik vaccine’s “fill and finish” process – where vaccine active ingredient is transformed into an injectible product. WHO voiced six concerns with the plant, including: “integrity of data and test results”; potential “cross-contamination” of the batches; and poor hygiene standards. The report followed a WHO-led inspection between the 31st of May and the 4th of June. The Ufa Vitamin Plant asserted in a statement on June 23 that the WHO concerns were addressed “within 48 hours”. “Following the receipt of the comments from WHO, Ufa VITA responded to all the questions and concerns raised within 48 hours,” the firm announced last week. “We invite WHO for another inspection. We remain fully transparent and will continue with the WHO prequalification process.” RDIF, however, has so far remained mum on the quality control issues raised by WHO – including non-response to queries by Health Policy Watch. And the WHO-reported concerns still remain outstanding, according to the public WHO dossier on the vaccine. WHO’s prequalification team flagged six concerns following its inspection of the Russian Ufa Vitamin Plant – a “fill-and-finish” facility Sputnik V Approval Process: “Additional Data Required” In response to a Health Policy Watch’s query, WHO declined to provide further clarifications, pointing only to its latest EUL update, dated 29 June, which continues to state, with respect to Sputnik V: “Additional data (Non-CLIN, CLIN, CMC) Required. Following up on inspection observations; Anticipated date [of approval] will be set once all data is submitted and followup of inspection observations completed.” “Subject to certain requirements being met, WHO will continue to assess Sputnik V vaccines from different manufacturing sites and will publish decisions on their EUL status when all the data are available and the review is concluded,” WHO’s latest news update on Sputnik also stated. Contamination Is a Common Concern Contamination is a common challenge faced by manufacturers of adenovirus-based vaccines, Ian Jones, Professor of Virology at the University of Reading in the UK, told Health Policy Watch. Potentially such contamination can make the adenovirus, which is supposed to remain non-infective, “replication-competent.” “The Sputnik V vaccine technology is basically just growing a virus,” he said. “However, it is not as trustworthy as the RNA as it is a biological, as opposed to chemical process. There are issues with yields, the risk of contamination and, for the adenovirus vectors [which deliver the vaccine], the need to measure the levels of ‘real’ adenovirus, a small amount of which is generated as part of the process. So, in many ways the older technology is a less good technology than mRNA technology.” Ensuring high hygiene standards in all vaccine production facilities, including fill-and-finish facilities, remains “very important”, emphasized Jones, to avoid contamination of batches with other pathogens as well. “High hygiene is very important in all such facilities to avoid bacterial contamination. The material will be injected, so passes the skin that normally acts as a barrier to pathogen entry,” he observed. Contamination is a common issue in the scale-up of adenovirus-based vaccines Pharma Manufacturers Say RDIF Issues Illustrate Challenges They Face Pharma leaders have repeatedly asserted that quality control issues, such as the ones identified by WHO at the RDIF plant, are illustrative of the challenges that they would face were they to issue open licenses as a means of scaling up vaccine production – as per the RDIF model. “It’s a very complex sector, with complicated science, very complicated manufacturing processes, we have to be very careful to whom we transfer the know-how, in particular because of the imperative of safety and quality,” said Bharat Biotech’s Executive Director of Quality Operations Sai Prasad, who is also President of the Developing Countries Vaccine Manufacturers’ Network (DCVMN), at an IFPMA-hosted webinar in late April. Bharat Biotech developed India’s first indigenous COVID vaccine – although that, too, has yet to gain WHO approval. “…. Don’t underestimate the requirements of standardized, manufacturing, quality control, and quality assurance,” Thomas Cueni, Director General of the International Federation of Pharmaceutical Producers (IFPMA), told Health Policy Watch in a recent interview. Stephane Bancel, CEO of Moderna Speaking at an April 2021 event, Moderna’s Stephane Bancel noted that technology transfers are a “matter of trust – trust between the partners but also patient trust: 70% of vaccine manufacturing is about quality control and quality assurance.” “That is why we should not get lost into thinking that intellectual property is the bottleneck. The limiting step is manufacturing know-how and capacity, ability to find skilled workers who can take part in the complex manufacturing process, as well as the raw materials.” “Basically companies have the responsibility for the quality of their products….Companies really need to have the ability to pick their partners on the basis of checklists, which is really about quality, quality, quality…” RDIF’s Has Little To Lose from Open Approach The Sputnik V vaccine uses twenty-year-old adenovirus technology, which lacks substantial intellectual property protections In fact, the RDIF has significant built-in incentives to try the open license approach – which western manufacturers may often lack, Knowledge Ecology International’s Director James Love told Health Policy Watch. “The RDIF lacks significant manufacturing capacity, does not think it is protecting a highly proprietary manufacturing platform, and sees a political benefit if having its vaccine being used,” emphasized Love. That is in contrast to companies such as Pfizer, Moderna, and other vaccine front runners, which already have significant manufacturing capacity – as well as novel technologies that they wish to protect, he said. And RDIF’s open license approach clearly has its limits as well. For example, the company has not shared its vaccine recipe to the WHO-backed COVID-19 Technology Access Pool (C-TAP), Love noted. Even though C-TAP was launched over a year ago, it remains empty to date of vaccine recipes from pharma developers in east or west, north or south. The RDIF also has given no signal, to date, about whether it would join the WHO co-sponsored global COVAX facility should its vaccine finally be approved by the WHO. “I don’t think the RDIF has suddenly become cuddly and philanthropic,” added Jones. “They want the hard currency the sales will bring…I think they also want to demonstrate that they can be a world player in the vaccine business [to become] a more permanent global supplier.” “Had they [Russia] invented a novel technology, it is not clear to me their current stance would have been taken.” -Elaine Ruth Fletcher contributed to this story. Image Credits: RDIF, Stelis BioSource, Wikimedia Commons. 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