Sterile Manufacturing - Contract Pharma

The pandemic offered many valuable lessons to pharma’s sterile fill and finish contractors, including how to refine processes to manufacture mRNA vaccines safely and dispense them to billions of patients at a record pace. The industry and its contract service providers proved more than equal to the challenge.

Perhaps the most crucial lesson being learned post-pandemic was just how valuable the collaboration with contract development and manufacturing organizations (CDMOs) turned out to be. By leveraging messenger RNA (mRNA) technology and commercial manufacturing partnerships, pharma companies were able to accelerate development and deliver an effective mRNA-based response to the virus.

With the help of their commercial partners, Moderna and Pfizer/BioNTech have been able to deliver more than 4 billion doses to patients to date. That’s a historic accomplishment and testimony to how valuable these relationships were to the industry. With the support of experienced sterile processing specialists, and aseptic manufacturing capabilities, pharmaceutical companies had immediate access to the infrastructure needed to develop mRNA vaccines and commercialize them successfully.

The many advances the industry made in its efforts to tackle coronavirus resulted in many, sometimes harsh lessons, but with this schooling, emerged a new development paradigm with better practices, new efficiencies and technologies including:

Flexibility: Capacity has to be flexible and dynamic to address the future needs of the market. Post-pandemic the flexibility and resiliency of the supply chain is also critical. How to scale up efficiently and be agile operationally to quickly address issues and opportunities is essential.

Diversity: Drugs intended for global markets demand flexible processing and manufacturing capabilities as well as advanced digital automation to handle the complexity and diversity of primary packaging ranging from vials and ampoules to prefilled syringes and cartridges.

Process insight: All the product’s chemistry and formulation attributes must be evaluated carefully, then optimized to reduce things like dead volume or maximize process flows.

With both EU and FDA approvals for its COVID-19 vaccine in hand, one innovator’s mRNA vaccine candidate was poised to be commercialized and distributed to global health care providers (HCPs) as quickly as possible. In keeping with contemporary drug development and commercialization business models, the decision was made to outsource, and the company engaged Recipharm and two other external manufacturing partners to deliver the capabilities and capacity to fill and finish its vaccine by the billions before the end of 2021.

Faster than the fastest virus
As one of the two mRNA vaccine candidates approved to fight the current strain of COVID-19, this vaccine developer was compelled to commercialize its formula as fast as feasibly possible. Once engaged, Recipharm quickly set upon the task to define the capacity and capabilities it would need to fill, finish and package the vaccine and meet the company’s ambitious development and commercialization goals.

Although preparing the formulation for commercial distribution was certainly a primary challenge it wasn’t the only one.

The tech transfer process also required flexibility, with Recipharm integrating peristaltic pumps in place of piston technology to handle the sensitive mRNA product by applying a gentle, consistent pumping force indirectly to the formulation.

Recipharm also had to work flexibly to overcome the temperature requirements - a maximum of 96 hours was allowed from the thawing of the drug substance to the final freezing of the drug product in secondary packaging. Exposing the formulation to room temperature conditions for longer than this period would impact stability and in turn efficacy of the vaccine.

Mid-2020, a leading U.S.-based clinical-stage mRNA medicines company asked Recipharm to support the manufacture of clinical trial supplies of a promising COVID-19 candidate destined for a pivotal Phase III trial.

The company engaged Recipharm to fill and finish 160,000 units of its mRNA vaccine and prepared the finished drug product for distribution to clinical Phase III trial patients.

Lyophilization emerges to innovate a solution
When the intellectual property owner presented its mRNA vaccine candidate for technology transfer it was originally proposed as an end-to-end fill, finish, and packaging project to deliver a ready-to-administer sterile, liquid injectable for clinical trial. But because of the inherent cryogenic logistics and storage costs associated with mRNA vaccines, as well its intended market (underserved populations with less access to developed healthcare infrastructures), a different approach was needed. As a result, lyophilization was chosen to ease the complexities of distribution and extend, without freezer storage, the shelf-life of vaccines at the point of care.

This innovation, developed in collaboration with the IP owner, was a unique first in the history of mRNA vaccines. Being a vaccine intended to fight a current strain, timelines were extremely tight and there was little room for error, let alone a major change to the vaccine’s Target Product Profile (TPP), during technology transfer.

Formulation complexities also added to the technology transfer challenges of the program. Originally the formulation called for manufactured lipid nanoparticles (LNP) to be combined in-train with mRNA from a third-party.

Engaging internal technical transfer development experts as well as the resources of the entire biochemistry department we were collectively able to identify the potential bottlenecks and quickly set hands on a viable solution.

Recipharm de-risked formulation processes and quickly integrated and optimized new LNP & mRNA combining processes. Chemistry, Manufacturing and Controls (CMC) filings quickly followed to validate the change to the original formulation during technology transfer.

Manufacturing and product handling must be super-efficient. Regardless of the batch size a manufacturer doesn’t have long from receiving the sterile product, filling, lyophilizing, and finishing each dose before performing secondary packaging. For any external contractor that means strict storage temperature requirements to be maintained at all times.

The vaccine program fully engaged the broad range of technologies including advanced digital manufacturing management platforms, a broad range of product and data analytics, and the site’s aseptic high-speed fill/finish and packing systems. On-site LnP mixing capabilities also proved effective. Ultimately tight collaboration and experienced capabilities combined to deliver the finished drug product on time and in full.

Megatrends in pharma have led to tremendous ongoing investment in sterile fill finish capacity and capabilities. These case studies demonstrate why the capacity provided by external partners is essential, because of how demanding, complex and costly operating sterile capacity efficiently can be. With the recognition that human beings present the most significant risk to contamination in an aseptic environment there has been a growing focus on applying technology to remove people from the process almost entirely. Rapid microbiological methods are also growing in popularity due to their ability to reduce manufacturing time and enhance the performance of environmental monitoring.

Today’s facilities are designed to ensure a high degree of segregation between process steps and to limit product exposure to the environment. To support this change, high levels of automation are being adopted to minimize operator intervention and, therefore, the risk of contamination. Additionally, regulatory requirements, such as EU GMP annex 1, are having a considerable impact on how the industry must approach processes within manufacturing facilities.

Post pandemic demand for aseptic manufacturing capacity for mRNA-based vaccines and therapeutics is likely to remain high. Outsourcing these capabilities to expert partners still represents the most cost-effective and time-efficient option for even the most prominent developers.

JON REED is Head of Strategy at Recipharm, a contract development and manufacturing organization (CDMO) headquartered in Stockholm, Sweden. Recipharm operates development and manufacturing facilities in France, Germany, India, Israel, Italy, Portugal, Spain, Sweden, the UK and the U.S.

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