Speed has been vital to saving lives during the Covid-19 pandemic, whether in the design of diagnostic tests, the development of vaccines or the delivery of life-saving equipment to hospitals. Speed, though, cannot come at the expense of rigorous research and quality control.
Finding the right balance has been hard, but the development and distribution of Covid-19 vaccines have put a spotlight on the pain points that slow down the manufacturing process. Overcoming those problems has led to invaluable insights into pharmaceutical manufacturing and, in particular, how the transfer of technical capabilities to outsourcing partners can be handled better in the future. One of the most important realisations has been that, for some of the complex Covid-19 vaccines and biological therapeutics, fast manufacturing requires not only an increased physical production capacity, but also access to knowledge not contained in patents or in other public disclosures.
Typically, the need to reverse-engineer originator companies’ manufacturing processes has been a major cause of both expense and delay in the creation of biosimilar products. However, the Covid-19 vaccine development process could herald a more collaborative approach across the industry and a new attitude to how critical technical knowledge is shared.
“A group of six biopharmaceutical firms researching monoclonal antibody candidates recently sought permission under antitrust law to exchange ‘technical information’ on each other’s manufacturing processes and platforms,” noted a recent paper entitled ‘Knowledge transfer for large-scale vaccine manufacturing’.
“A focus on rapid information exchange of the sort recently encouraged by the [US Department of Justice] will not only be critical for the current crisis, but could also create the foundation for fewer silos, improved standardisation and less secrecy over manufacturing information in the future,” the report says.
Delays can be deadly
More open knowledge transfer can greatly increase the speed and scale of manufacturing processes, but in normal times this is a competitive market with closely guarded intellectual property. The pandemic has shown the need to bend traditional rules, though there have still been some notable refusals. For instance, Inovio claimed in a June 2020 court filing that its own experimental vaccine was being “held hostage” by a contract manufacturer unwilling to share details of its manufacturing process.
Even when lines of communication between pharma companies and their contract manufacturers are open, the transfer of technical know-how can still cause delays. A recent McKinsey report, based on from a survey of vaccine manufacturers, highlighted that the technical transfer process can typically take between 18 and 30 months. That’s too long under normal circumstances, so it’s certainly too long during a pandemic.
Technical transfer is the bridge between development and manufacturing. It determines how quickly a new product will come to market, but until recently its importance has, it seems, been underappreciated – not least because it is not front of mind during the development stage. Ensuring adequate and timely supplies of Covid-19 vaccines has required unprecedented collaboration between global institutions, pharma companies and their contract development and manufacturing companies (CDMOs). This is proof that the tech transfer phase can be expedited when necessary.
“The relationships we have with CDMOs are very important for us, as we rely on outsourcing for all process development, analytical characterisation, quality control and manufacturing,” says Michael Mulkerrin, vice-president and head of chemistry manufacturing and control (CMC) at ADC Therapeutics. “We look for a partner who has significant expertise in their area. We depend on the contractor or CDMO to be able to develop assays or processes and contribute to the understanding of the development.”
Mulkerrin is emphasising the critical nature of the CDMO relationship, which has been accentuated across the industry, with the crisis of Covid-19 acting as a catalyst to bring vaccines to market much faster than usual. As the McKinsey report noted, large biopharmaceutical companies are now willing to share information that they would have previously seen as a threat to their competitive advantage.
18–30
Number of months the technical transfer process can typically take.
McKinsey & Company
They may even be willing to pursue some standardisation of how such information is shared, which could lead to a more uniform vaccine manufacturing process. As some platforms, such as mRNA, have never been produced at scale before, this could prove crucial in the future.
Though the pandemic does represent a set of exceptional circumstances, in which secrecy around manufacturing processes would have been catastrophic, it also shows how sharing relevant information can lead to the quick and effective scale-up of production. The next step is ensuring that the CDMO responsible for production can handle the processes and ramp up production swiftly without compromising quality. As Mulkerrin suggests, the quality of the relationship with the CDMO is of paramount importance. His company, which creates antibody-drug conjugates (ADCs) to deliver pyrrolobenzodiazepine (PBD) dimers for cancer therapy, has a carefully planned approach to the technical transfer process, which is based both on thorough technical processes and, to some extent, an assessment of the cultural fit with its CDMO.
“We set up the tech transfer by creating an overriding document and then one for each unit component of the manufacturing, such as upstream, downstream, conjugation, and fill and finish,” Mulkerrin explains. “Then we have a meeting, typically a day or perhaps two, after two on-site at the manufacturer.”
“There is a component that is cultural, but clearly it is mostly technical,” he adds. “Our internal alignment is within the manufacturing group for the manufacturing, as well as with the regulatory and quality organisations. The same is true for the quality control group. We rely on the experts to help each other and as long as there is respect for the organisation then it will run smoothly.”
Essential steps to streamline tech transfer
While the pandemic has highlighted the need for speed in all stages of vaccine production and manufacturing, and it has cast a light on the areas where delays arise, it must be remembered that the window for tech transfer in the vaccine development process was already narrowing. Ten years ago, it might have been normal for a full tech transfer to take between five and ten years. In that context, 30 months does not seem long at all.
Nevertheless, that trend of acceleration must continue, and the pandemic has shown that it can. Tech transfers involve many challenges – not least the need to account for the safety, quality, and efficacy requirements of life-saving products that can, at the same time, be potentially toxic. That places a great burden on the production process, as does the complexity of the manufacturing process, which requires a large team of highly skilled experts striving for the highest quality standards.
So, what kind of steps can be taken to streamline the tech transfer process and shorten timelines for production? McKinsey’s researchers have looked closely at this problem and identified key parameters that, though familiar to ADC and others, are now more clearly codified.
Many of the steps relate to early planning and instituting a process for rapid decision making. From the start, the pharmaceutical company should define a clear end-to-end strategy, detailing even the contract manufacturing phase. Standardised documentation for feasibility evaluation, as well as early clarification of filing requirements and country-specific issues are also high on McKinsey’s list of priorities. Other factors, however, stem from a pharmaceutical company’s relationship with its CDMO. These include the need to work in partnership to identify risks in the transfer process and to instil a mindset of continuous improvement. Taking every step will not eliminate every hurdle, but it will go a long way to making a tech transfer both swift and successful.
“For early programmes, we can encounter problems in the development of a process, but for our later programmes we expect the surprises to come much less often,” says Mulkerrin. “In a good relationship we expect the problems to be worked on as a collaboration, with both sides contributing to the solution. It is with new programmes that the industry usually encounters problems.”
“Our evaluation of a CDMO begins with an assessment with a team travelling to the site,” he adds. “Then we have an RFP [request for proposal] they answer, and the depth and clarity of the response is part of the evaluation. Then the quality assurance organisation will audit the company. Each of these steps in our evaluation permits us to understand the organisation we are evaluating. We value the technical capability and their quality temperament the most.”
The pandemic has emphasised the need for tech transfers to be seen as an opportunity for streamlining the production process at scale, rather than as a bottleneck. This applies directly to Covid- 19 vaccines and therapeutics, but a push for more standardised methods for sharing information and manufacturing know-how could have far-reaching implications across the industry. Technical transfer, with the right strategic planning early on and a clear process for assessing the CDMO relationship, can be an opportunity to make products and processes better, rather than just another hurdle to clear.
Production process challenges for biopharmaceuticals
- Molecule or virus complexity: 2,500–25,000 atoms in protein-based vaccines; even greater complexity in virus-based vaccines, creating a highvalue product.
- Molecule or virus stability: great sensitivity to heat, pH and organic solvents, possibly resulting in a relatively short shelf life.
- Production principle: recombinant technology, typically with >15 steps or sterile design for drug substance and drug product, involving complicated and expensive production requirements.
- Scalability: difficult, up to approximately 20,000L, meaning there is limited output per production line.
- Cell banking: sterile handling and master cell banks needing to be maintained at temperatures as low as –120°C.
- Raw materials: typically >50 raw materials with many critical specs, creating a heavy test load on raw materials and difficult quality control.
- Purification: multistep chromatography, an expensive step with high-cost consumables.
- Lead time to drug substance: often long, measured in weeks or months.
- Storage: cold room (2–8°C) and frozen storage mean tight supply chain control is required.
- Transport: cold chain transport in frozen state for drug substance and at 2–8°C for drug products mean tight transport control is required.
Source: McKinsey & Company
