If you’re a U.S.-based pharmaceutical executive in charge, in any way, of manufacturing, it’s likely you haven’t seen a lot of blow-fill-seal (BFS) technology installations. That’s not to say they don’t exist, especially considering the technology has been around since the 1930s. But it is still not as prevalent in U.S. pharmaceutical manufacturing as you would think, which is why I’ve asked two experts in the field to explain the business benefits of this unique and useful aseptic processing technology. Tim Kram is the general manager of rommelag USA, and Chuck Reed is the director of sales and marketing at Weiler Engineering. Both rommelag and Weiler manufacture BFS equipment.
First, you should understand what BFS technology is and how it’s different from traditional aseptic filling. With BFS, during one continual process, the plastic for the container is extruded and formed into the shape of the container, filled, and then sealed. It’s a fully automated process that takes about 15 seconds to complete.
In general, a traditional aseptic filling process has up to 12 steps, involves numerous people, and — when considering the vial formation in clean conditions, bulk packaging, transport, and storage — can take months to complete.
WHY HAS BLOW-FILL-SEAL TECHNOLOGY BEEN MORE WIDELY ADOPTED IN EUROPE THAN IN THE UNITED STATES?
Kram: When a new product goes into Phase 3 clinical trials, a decision is made to place the product into its final packaging. In most cases, BFS containers are not considered. There are several reasons for this exclusion, including the presence of existing packaging equipment, picking packaging that is similar to other products that are on the market, lack of knowledge about BFS, and preconceived notions about BFS. Once a product is in a particular packaging, it is rare to have that packaging process changed. Thus, generic versions follow in the same packaging form. The key for BFS is early acceptance in a product’s life.
I consider advanced aseptic isolator/filler technology to also be an underutilized technology in the United States that is better accepted in Europe. The USP (United States Pharmacopeia) and the FDA only accept BFS and isolator/filler systems as advanced aseptic technologies.
Reed: BFS technology has been accepted internationally, including a large installed base in the United States. The distinction is in the market penetration. In North America, respiratory therapy and ophthalmic applications are most common with virtually no injectable products produced by BFS (with the exception of some veterinary products). Outside of North America, it is more common to see BFS used for injectable products in addition to the other products.
WHAT ARE THE KEY BUSINESS BENEFITS OF BFS TECHNOLOGY?
Kram: The higher automation of BFS results in a lower labor requirement. Furthermore, you also have reduced facility-related costs due to a smaller footprint than traditional aseptic filling, a smaller warehouse for raw materials, and a reduced utility consumption (no WFI [water for injection] washing requirement). BFS also produces a very high overall equipment effectiveness (OEE), resulting in higher outputs for investment.
Reed: A huge advantage of BFS is the removal of the human element from the process. The regulatory agencies all recognize that human intervention is the major cause of sterility failures in all critical processes.
The second big benefit of BFS is the savings realized from producing a complete finished product in one machine frame. Elimination of the costly processes of vial/bottle inventory, cleaning, sterilizing, separate filling operations, and separate capping operations are accomplished with BFS.
WHAT ARE THE MOST COMMON OBJECTIONS TO ADOPTING THIS TECHNOLOGY?
Kram: The number one objection is simply that many companies don’t even consider BFS in the first place. Second, they often feel there is incompatibility between the container and product. (To improve compatibility we have developed BFS Co-Extrusion technology. This enables customers to custom design the plastic container with barrier and compatibility layers.) The final objection is related to the costs associated with changing to the technology.
Reed: First, there is a significant installed base of conventional filling technology. Second, it is easier, with less risk, to continue to promote an existing process rather than qualify a new process with the regulatory agencies. There is much more willingness internationally to adopt new technologies.
IN THE PHARMA AND BIOTECH INDUSTRIES, WHAT ARE THE BIGGEST AREAS OF GROWTH FOR BFS TECHNOLOGY? IN OTHER WORDS, WHAT TYPES OF PRODUCTS ARE YOU SEEING AN INCREASED INTEREST IN FOR THIS TECHNOLOGY?
Kram: For BFS, unit/single-dose is where we have strength, and we see growth. From vaccines to oral dose drugs, there is a need to move away from multidose formats. In the developing world, there is a great benefit from packing drugs in their final unit-dose form. BFS containers are also tamper-evident, heat/cold stable, and very resistant to breakage.
We also have multidose formats that provide alternatives to conventional container types — SVP (small-volume parenterals) and ophthalmic products are good examples.
LVP (large-volume parenterals) products have been on a growth cycle since the 1970s. The largest IV facility in Europe utilizes BFS technology.
And finally, biological products, if compatible with plastic, have benefits in BFS containers. There is only one product contact layer, the containers are cold-compatible, and they can accurately deliver very small doses (1 to 200 microliters).
Reed: We anticipate growth in the unit-dose marketplace for many products. We also see growth in generics and increased interest in parenteral (injectable) products, as well as biologics.
IS THE FDA DOCUMENT, “STERILE DRUG PRODUCTS PRODUCED BY ASEPTIC PROCESSING — CURRENT GOOD MANUFACTURING PRACTICE,” THE MOST RECENT FDA-RELATED INFO ON THIS TECHNOLOGY? WHAT SHOULD EXECUTIVES KNOW ABOUT THIS DOCUMENT?
Kram: This is the current guidance that relates to BFS technology. Pharma executives should know that BFS is specifically called out in Appendix 2. It comes from BFS users working with the FDA to get the technology better acceptance. Prior to this guidance, BFS was considered under rules that did not necessarily apply to the technology. This left users to explain why the rules did not apply to their BFS machines. This guidance, by defining the BFS process, highlighting the technolgy’s strengths, and directly addressing BFS in a way that reduced uncertainty, has allowed users to have more confidence in BFS use.
Reed: This is the current U.S. regulatory authority guidance, but it is not the only source. USP, EMEA (European Medicines Agency), and other regulatory agencies have published pertinent documentation.