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The continuous, aseptic fill/finish process is finding use in vaccines and biologic drugs.
Blow-fill-seal (BFS) equipment has been widely used for many years in aseptic fill/finish of small-molecule and biologic liquid formulations, including nebulizer solutions for respiratory delivery and ophthalmic sterile solutions packaged as unit-doses. A key advantage of the process is that it is a closed, automated system—a plastic container is formed within the equipment, filled with sterile solution, and closed, with limited human intervention. Although concerns about process temperatures caused hesitancy with some manufacturers of temperature-sensitive biologic drug products, understanding and control of these issues has significantly increased. As a result, more manufacturers are considering BFS as an option for fill/finish of vaccines and other biologic drug products, including large-volume and small-volume parenteral injectable drug products.
In addition to being an efficient, closed aseptic system, another benefit of the BFS process is the ability to handle unique or complex containers that can be designed for a specific need. For example, GlaxoSmithKline’s (GSK) oral rotavirus vaccine in unit-dose BFS containers was designed in collaboration with global health organization PATH and used for the first time in February 2020 in an immunization program in Myanmar (1). The container is formed as five single doses in a connected pack of tubes that can be separated for individual oral delivery. The container was designed to be less bulky than conventional vaccine squeeze tubes, which makes it easier to transport and store and reduces cold-chain costs.
“The container in a BFS process can be designed to be functional for delivery to the patient,” says Andy Goll, president of Weiler Engineering, Inc., which designs and supplies BFS equipment as well as using the equipment for fill/finish as a contract development and manufacturing organization (CDMO). “For oral delivery to young children, for example, the GSK rotavirus vaccine container was designed with a longer, narrow tube for the opening so that it would fit well inside the child’s cheek. Containers for injectable vaccines can be designed to fit to a separate needle hub.”
“Some of the benefits of BFS aseptic packaging include limited human intervention on the filling line, efficient production of unit-dose containers at high volumes, ability to rapidly scale production for surge capacity, and a consolidated materials supply chain that helps decrease reliance on external sources,” says Josh Myers, senior director, Supply Chain, ApiJect.
“Single-dose containers reduce the wastage found in multi-dose glass formats commonly used with vaccines,” adds Tim Kram, managing director at BFS equipment manufacturer Rommelag Engineering. “BFS systems are compatible with disposable filling systems, which minimize product loss during filling.” The most significant benefit, says Kram, is having a fully automated system, which reduces risks in the aseptic process.
BFS reduces the risk of microbial and foreign particulate contamination when compared to traditional glass vial fill/finish processes, adds Waiken Wong, manager of Development Engineering at CDMO Woodstock Sterile Solutions.
In the BFS process, the plastic raw material is melted, extruded into a cylindrical tube (called a parison), and formed into a container by blowing sterile air or nitrogen into the tube to force the plastic into the shape of the mold. Cooling of the container begins within seconds after it is formed, because the mold is chilled. The drug solution is then filled into the just-formed plastic container while still inside the mold, and the container is sealed. The form, fill, and seal steps typically take less than 15 seconds.
“Essentially, you have to manage process parameters to cool the container before the drug product contacts the internal surface,” explains Goll. “There are multiple ways to control the container temperature by controlling the cooling and blowing process. Not having to worry about heat degrading a vaccine is a game-changer in the ability to use BFS.”
Polymers typically used in BFS containers are low-density polyethylene (LDPE), high-density polyethylene (HDPE), and polypropylene (PP). “LDPE is typically used for containers for large-molecule drugs or vaccines, because it can be extruded at a lower temperature than HDPE or PP. A lower processing temperature makes it easier to obtain an appropriate surface temperature for filling,” explains Goll. PP would be used for drugs that require terminal sterilization, as it can withstand higher temperatures during the terminal sterilization process.
Goll says that interest in BFS for fill/finish is rising as manufacturers recognize its potential, particularly for the flexibility of the types of containers that can be filled. Weiler is performing feasibility studies for potential users who want to switch from a conventionally filled glass container to a BFS plastic container. The first step, he explains, is to check compatibility of the drug product and the container, including evaluating the extractables and leachables and product stability, typically using accelerated stability studies. Next, the container shape, including its opening, closure, and any separate adapters, is designed and a mold is made for the specific container shape. In the subsequent engineering design phase, the equipment and the process are optimized for the product. An advantage of the Weiler carriage (i.e., shuttle) system is the flexibility to easily change the mold size or shape, although it is not as high speed as a rotary BFS equipment setup, says Goll.
“Biomolecules can have some affinity for olefinic [LDPE, HDPE, and PP] materials, so stability studies are needed to ensure adsorption or absorption effects don’t impact therapeutic dose or activity levels,” adds Wong. Effects from gas and water vapor permeation through the walls of BFS containers may also need to be assessed in a stability program. Both standalone and comparative stability studies with glass are needed to demonstrate that plastic is an acceptable alternative.
“Many of the challenges a drug product developer faces when considering BFS are the same for traditional filling lines, such as glass vials,” adds Myers. “What is most important to remember, regardless of filling process, is that careful evaluation and grasp of the key parameters and process characteristics will allow for appropriate selection and risk mitigation.”
Temperature is one aspect that includes not only temperatures during filling, but also in mixing prior to filling and in post-filling activities. All materials that the drug product will come into contact with should be reviewed, along with cleaning procedures and transportation and storage of raw materials and finished products, says Myers. Modes of sterilization, heat mitigation, and protecting oxygen and light sensitive drugs all need to be considered. For plastic containers, foil wraps are often used to reduce exposure to UV light and oxygen and to reduce any potential vapor loss, adds Myers.
Kram adds that there are two primary methods to keep the product cool while using BFS technology. “The first does the most work, keeping the product at a low temperature (e.g., 2–5 °C) while in the batch holding tank, and controlling the temperature from the tank to the point of fill. By prechilling the product the final temperature can be kept in an acceptable range,” he explains. The second method is through container design.
Woodstock Sterile Solutions, which is the new name of the former Catalent BFS CDMO business that was acquired by a private investment firm in 2021 (2), was granted a US patent for a new, “cold” BFS process (3) that builds on its 50-year experience with using BFS for filling respiratory, ophthalmic, topical, otic, and oral drugs. The new process is designed to minimize the impact of temperature on thermally sensitive molecules.
“Our cold system comprises a combination of optimized process parameters that together reduce the exposure of the drug product to potentially detrimental temperatures,” explains Wong. “These parameters are from points throughout the manufacturing process, from the bulk product in the holding tank to the final sealing of the BFS container. The goal is to optimize the conditions to provide the best level of control.”
Wong says that the process has been evaluated for filling a monoclonal antibody and in exploratory studies for vaccines. He says that multiple programs, ranging from early- to late-stage clinical, are using the process.
As BFS expands into more biologic drug products and vaccines, the opportunity is opening up for new delivery systems. Packaging an injectable product with a BFS process in a plastic ampoule is not new. What is new, however, is ApiJect’s prefilled injector that connects an intramuscular needle hub to a BFS single-dose container. In this case, the fit of the needle hub onto the container to make the complete drug delivery system must also be considered, says Myers. When filling an injectable drug product, there may be additional requirements for the biosafety level of the environment and visual inspection, adds Myers.
The prefilled injector technology in development by ApiJect is designed to be a cost-effective drug delivery system to manufacture and be lightweight for lower transportation costs. The single-dose format has advantages for safety, sterility, and low waste, which are especially important in low-resource, developing regions (4). While the drug delivery system was developed prior to the COVID-19 pandemic, the concept of being able to produce prefilled syringes on demand was seen as a potential solution to the concerns about possible vaccine container shortages in the midst of the pandemic in 2020, and the US Department of Defense awarded a contract to ApiJect to expand US production capability of up to 45 million doses per month in Biosafety Level 2 cleanrooms at The Ritedose Corporation in Columbia, SC (5). Although the emergency fill/finish capability in the United States was prepared in 2020, it did not end up being used for COVID-19 vaccine filling as the device has not been cleared by FDA. The technology, however, is available for drug manufacturers to evaluate.
Today, ApiJect continues to have operation capacity for development and commercial work at The Ritedose facility. In addition, in December 2021, French CDMO Fareva and ApiJect announced a 10-year licensing agreement to install BFS production lines with the capacity to fill/finish 500 million doses per year of vaccines and other large-molecule injectable drugs with ApiJect’s technology (6). BFS machines from Rommelag in Germany will be installed in Biosafety Level 2 cleanrooms. Fareva and ApiJect plan to produce validation batches in 2022. This type of “distributed fill/finish” capability aims to strengthen local supply chains.
1. PATH, “Myanamar’s Rotavirus Vaccine Campaign First to Use New Delivery Technology,” defeatdd.org, Mar. 12, 2020.
2. SK Capital, “SK Capital Closes Acquisition of Catalent’s Blow-Fill-Seal Sterile CDMO Business and Changes Name to Woodstock Sterile Solutions,” Press Release, March 31, 2021.
3. Woodstock Sterile Solutions, “Woodstock Sterile Solutions Granted US Patent for Cold Blow-Fill-Seal Packaging System and Process,” Press Release, Dec. 9, 2021.
4. ApiJect, “A New Way to Inject and Track Vaccines that Can Reach Everyone” dcvmn.org (2019).
5. DOD, “DOD Awards $138 Million Contract Enabling Prefilled Syringes for Future COVID-19 Vaccine,” Press Release, May 12, 2020.
6. Fareva, “Fareva and ApiJect Sign a Licensing Agreement to Create a France-based 500M Unit Annual Capacity for Single-vDose Prefilled Vaccine Injections,” Press Release, Dec. 9, 2021.
Jennifer Markarian is Manufacturing Editor for BioPharm International.
Vol. 35, No. 3
When referring to this article, please cite it as J. Markarian, “Considering Blow-Fill-Seal for Biologic Drugs,” BioPharm International, 34(9) 2022.