Fill/Finish: Increasing Investment and Flexibility for Effective Manufacturing

The global biopharmaceutical market is expected to experience rapid growth over the next decade. To prepare for this impending demand, pharmaceutical manufacturers are investing heavily in cutting-edge aseptic fill/finish technologies to increase production efficiency and efficacy. 

Market Growth

Adopting new methods of development ushers in a new set of challenges, however, which is why partnering with an industry leader in fill/finish is the key to achieving and guaranteeing success. With the expansion of our Baltimore Camden facility, Emergent BioSolutions has committed $50 million into meeting the market’s needs by updating our fill/finish technology. We see this as the necessary investment to meet demand.

According to a recent report published by trend forecasting company Allied Market Research, the total biologics market was valued at $186 billion in 2017 and is predicted to be worth $526 billion by 2025, with a compound annual growth rate (CAGR) of 13.8%. The bulk of that anticipated revenue is associated with the North American market.1 

The market growth of biologic products is attributed to a range of factors, including changes in population demographics. As the elderly population continues to grow internationally, there has also been a corresponding increase in obesity and diagnoses of chronic illnesses, such as cancer. Unsurprisingly, the demand from emerging markets, including China and India, has also contributed to the steady and upward growth of biologics. Within the biopharmaceutical market, the monoclonal antibody segment is expected to dominate, with metabolic disease applications growing at the highest CAGR.1

Fill/Finish Sterilization Methods

In keeping up with this growth, manufacturers need to continue to respond to and abide by the rigorous handling and packaging regulatory demands of biologic production. The U.S. Food and Drug Administration (FDA) has previously mandated that all equipment used in biomanufacturing must be sterilized before it touches the drug product. Tactics for ensuring sterilization are cost and energy intensive, and common sterilization options include the use of steam autoclaves and dry heat. Treatment by irradiation is another method for achieving this process. 

Since all equipment must be sterilized before it can enter a cleanroom, knowledge and familiarity with all sterilization techniques is key. The chosen route of sterilization not only impacts the formulation, but it also affects the contaminants present on the equipment in differing ways. Currently, the most common sterilization method is steam autoclaving. Although this technique eliminates many pathogens, there is still a risk of degradation of more sensitive components of the formulation (such as amino acids), as well as of other tools and packaging components that are sensitive to heat and moisture. 

Dry heat ovens are an alternative to steam autoclaves. In dry heat ovens, the equipment is sterilized in batches or in a tunnel, where very hot dry air is circulated. While this method can cause damage to temperature-sensitive formulations or equipment, it eliminates the need to expose the products to moisture. 

Radiation sterilization technology has also been adopted more widely over the last several years because it produces highly effective results. Ionizing and gamma radiation destroy bacteria that can survive heat sterilization; this type of radiation also has a higher penetration rate. The downside to using radiation sterilization, however, is the potential impact of irradiated particles on the formulation. 

It is crucial that the relative advantages and issues associated with each sterilization option are weighed before moving ahead with production.

With the Expansion of our Baltimore Camden Facility, Emergent Biosolutions has Committed $50 Million into Meeting the Market’s Needs by Updating Our Fill/Finish Technology

Designing a Cleanroom Facility and the Lyophilization Phase 

Before packaging or bottling, most biologics must be lyophilized. Lyophilization is a constraining and intensive process that contributes to even greater fill/finish challenges. During lyophilization, manufacturers may rely on automated or semi-automated loading procedures. In this process, vials are prepared in batches, loaded into a lyophilizer and exposed to a freezing stage in tandem with the formulation. Next, the lyophilized drug is loaded into the vial, which is then stoppered. In this method, aseptic fill/finish is achieved without separating the drug product, which reduces the risk of outside contamination. 

All sterilization activities take place in the cleanroom, which must also be designed for optimal sterilization. Every detail must be considered when setting up a cleanroom. For instance, the air that circulates in a cleanroom must first pass through a high-efficiency particulate air (HEPA) filtration system, as even seemingly innocuous particles can be contaminants in this high-stakes, high-value environment. The cleanroom layout must also embed work activity, with areas of high sterility kept separate from sections that have lower sterility requirements, in order to prevent any contact that may lead to contamination. This includes the sectioning off of aluminum, which can contaminate certain types of equipment, particularly stoppering equipment. 

Single-Use Systems, Pre-filled Syringes and Automation

In addition to factoring in a cleanroom’s layout, sterilization methods and the lyophilization process, drug manufacturers must also consider the equipment they use in fill/finish production, which should be flexible enough to meet varying drug product manufacturing demands. The adoption of innovative technologies, such as single-use systems made of disposable polymers, aseptic fill syringes and automated or semi-automated filling processes, allows for upgrades to production — though these techniques also introduce new risks. 

In single-use systems, more traditional stainless steel filling equipment is swapped out for plastic parts. With this replacement, there is no need to continuously sterilize the equipment. This eliminates the need for energy and time-intensive processes, such as autoclaving or dry heat circulation and for moisture and the sterilization of equipment between batches. Employing a single-use system also frees up crucial space on the factory floor. 

Demand is also growing for the replacement of traditional vials with pre-filled syringes. Through the use of pre-filled syringes, waste is minimized and the chance of accidental overflow or contamination of vials is eradicated. With a pre-sterilized syringe, there is no need to repeat sterilization or fill a dose into a vial. Pre-filled syringes are also advantageous because they can be incorporated into production at any scale, from small batches to commercial production. Biologic pre-filled syringes also reach their endpoints faster than traditional syringes and pose minimal risk of contamination. For manufacturers that must demonstrate extreme precision in their packaging stage, pre-filled syringes are an especially desirable option.

A growing trend throughout the supply chain, automation is a means to speed up time to market and increase efficiency. Automation is attractive for a number of reasons, primarily because it minimizes human interaction and thus interference. Automation also reduces the number of personnel needed to complete a process, which contributes to lower costs and helps to maintain consistency of quality. As automation enables continuous processing, more product can be produced in the same time period than with manual production. The downside of automation, however, is that it is a fixed process and therefore lacks the flexibility implicit in human operation, especially if an unforeseeable event occurs. 

Biologics manufacturers that partner with fill/finish experts obtain a significant advantage in the market, given the stringent regulatory demands that are tied to the sterilization process and the nuances of sterilization methods that can impact a formulation at all phases of production.

Investing in Fill/finish Capacity

Biologics manufacturers that partner with fill/finish experts obtain a significant advantage in the market, given the stringent regulatory demands that are tied to the sterilization process and the nuances of sterilization methods that can impact a formulation at all phases of production. In order to meet more of our partners’ needs more effectively, Emergent BioSolutions has invested $50 million into the expansion of our Camden facility located in Baltimore, Maryland. This expansion began in June 2018 and will be completed by 2021. This integrated, multi-year commitment will significantly increase our capacity, benefitting our existing partners and attracting other industry leaders to our site as we lead in the advancement of biotechnology. 

One of the highlights of the expansion is the addition of a new isolator-enclosed fill line. In our partnership with Groninger & Co., we installed their FlexPro 50 filler with isolator technology and an integrated Martin Christ lyophilizer. This new fill line will be capable of filling vials, syringes and cartridges — all with dedicated utilities. We will also be adding a second autoclave to the site, which will provide increased sterilization capacity. Additionally, the site will now house a new cold storage space, which will support 2–8 °C and –20 °C requirements. The expansion will also include new stability chambers, new media fill incubators and additional warehousing and office space. Not only will the facility contribute to boosting Emergent BioSolutions’ positioning in the area of fill/finish, but the expansion will also contribute to the local and national economy. Our plan is estimated to add up to 60 new jobs over the life of the three-year project. 

At Emergent BioSolutions, we are looking forward to continuing our aseptic fill/finish operations and working closely with our clients, in order to fulfill our mission — to protect and enhance life. The planned ongoing expansion at our Camden facility will increase our contract development and manufacturing capabilities significantly, not only bolstering our company’s output but also contributing to the industry on a much wider scale. 

References

  1. Global Biopharmaceuticals Market Expected to Reach $526,008 Million, by 2025 |CAGR 13.8%. Allied Market Research. 16 Jul. 2018. Web.

B.J. Hull

B.J. Hull has over 25 years of experience in manufacturing, external manufacturing, quality, engineering, operational excellence and distribution in fast-paced, cGMP-regulated facilities. He has significant pharmaceutical leadership experience and has previously held the manufacturing site head role with full P&L responsibility for Gilead Science, Sandoz and Mallinckrodt.