In an aseptic process, the drug product, container, and closure are subjected to sterilization methods separately, as appropriate, and then brought together. Because there is no process to sterilize the product in its final container, it is critical that containers be filled and sealed in an extremely high-quality environment. Aseptic processing involves more variables than terminal sterilization. Before aseptic assembly into a final product, the individual parts of the final product are generally subjected to various sterilization processes.
For example, glass containers are subjected to dry heat; rubber closures to moist heat; and liquid dosage forms are subjected to filtration. Each of these manufacturing processes requires validation and control. Each process could introduce an error that ultimately could lead to the distribution of a contaminated product. Any manual or mechanical manipulation of the sterilized drug, components, containers, or closures prior to or during aseptic assembly poses the risk of contamination.1
To discuss some of these issues, recent trends and future outlook of the aseptic filling market, Pharmaceutical Processing spoke to several industry vendors to get their insight into this highly technical and important process.
With the continued emphasis on biotech and biopharmaceutical products it’s only natural that manufacturers of aseptic filling equipment are seeing an explosion in the filling of these new types of drugs. And, as these drugs are often small batches of high value products, there has been a discernable shift in priorities.
As Jeff Jackson, Director of Project Management and Sales at Bosch Packaging Technology (www.boschpackaging.com) explains, “The biggest trend right now is reducing loss when filling high value products. We are seeing smaller batches and smaller fill volumes. Companies are very concerned about minimizing waste and maximizing yield. In addition, set-up of fluid paths is very important as is checkweighing. We see companies doing 100% checkweighing at the start of filling and then at the end to make sure every drop of high-value product is used."
Jackson continues, "Two trends are making themselves apparent: The first is clinical filling of small batches is increasing; companies want to get people out of this process and make it more automatic. The goal is to “clean-up” the process; and second, added flexibility with equipment – we are seeing a trend towards more flexibility in batch sizes and container sizes.”
“There is a shift happening in the types of containers being filled," notes Dr. Wenzel Novak, Director Pharmaceutical Research and Development at groninger & co. gmbh (www.groninger.de). “This is due to the emphasis on smaller batches of biotech products. These products are expensive.” He continues, “we are seeing more automation, and an emphasis on closed RABS processing and the use of isolators. These changes are to keep the operator out of the process. This is a quality driven development to remove any manual handling of product. We are also seeing a trend in machine design to handle different containers on one machine such as syringes, vials, etc. There is certainly a drive to be more flexible.”
Regarding the use of isolators and containment technologies for aseptic filling, Gary Partington, Walker Barrier Systems (www.walkerbarrier.com) offers, “As a company that provides isolator enclosures that are designed to protect the product from the operator, we work closely with filling equipment vendors to make isolator ready equipment. It’s very important to make sure filling equipment “mates up” properly with isolators and to ensure a proper ergonomic design. In most cases we use mock-ups to ensure accuracy."
"The global use of isolators on filling lines is definitely growing and the trend is to combine both technologies – filling equipment and isolators. And the FDA is becoming more and more accepting of this technology and is strongly encouraging the industry to adopt these technologies as the way to move forward.” Partington adds.
Vial filling machine isolator is used to fill small volume batches of a potent liquid drug aseptically. The isolator operates under positive pressure with uni-directional airflow and has an emergency negative pressure system. (Photo courtesy: Walker Barrier Systems)
“The big trend right now with biotech filling is that all products have to be filled aseptically and can’t be terminally sterilized," says Marc Michael Machauer, Sales Manager at OPTIMA GROUP pharma (www.optima-packaging-group.de). “We are also seeing a trend that machines are required to be perfect and run without operator intervention. Volumes are getting smaller. Years ago volumes were higher, now we have drugs with higher concentrations. Machines need to be more flexible. Biotech products are sometimes made in 20 - 30 different combinations – customers need different containers which necessitates frequent changeover. We are seeing a change to smart changeovers and smart filling machines that don’t need changeover parts for new containers. In some cases this new breed of machines can go up to three weeks without being opened.”
For an alternative view of aseptic filling trends we spoke to Tim Kram of rommelag (www.rommelag.com) a manufacturer of blow/fill/seal equipment for his take on the latest trends. “Traditional blow/fill/seal equipment has been used for inhalation, ophthalmic and unit dose products. Now we are seeing a growing trend towards biotech products - specifically small volume parenterals such as injectables. We are putting a lot of emphasis on vaccines – as we see this as a big growth area.”
More biotech products are now being filled in unit-dose containers like those show here. (Photos courtesy: rommelag)
As the market for biopharmaceuticals filled aseptically expands, so does the scrutiny of these products. And, as the market for products is no longer primarily U.S. based companies are struggling with international regulations. As Jackson from Bosch points out. “We see our customers struggling with products for export – trying to be flexible. There is also the issue of getting multiple approvals from multiple agencies such as those in the EU and Japan.”
Regarding technology and the FDA, Optima's Machauer says, “Aseptic guidelines from the FDA are not new. The FDA knows the technology. Pharma companies have to realize they can’t make old machines work simply by retrofitting.”
And finally on the subject of the FDA's QbD iniative, groninger’s Wenzel has this to offer, “QbD might be the name the FDA has given to their initiative, but the basic idea has been around for a long time and we have been incorporating QbD features for awhile.”
With more emphasis on high-value biotech products, the aseptic filling market is increasingly turning to various new technologies to meet business needs. Looking toward the future our industry experts see disposables and flexible/highly precise machines as two future trends.
“Single-use is definitely the way of the future,” says Bosch’s Jackson. “We see single-use equipment being used all through the filling line. It makes financial sense, especially since the need for cleaning goes away. The use of disposables also adds the element of flexibility which is so important.”
Groninger’s Wenzel also views disposables as a future trend. “We definitely see the future of aseptic filling as one that features more use of single use equipment for fluid paths, pumps and filling needles. All of this is driven by a desire to eliminate any need for cleaning validation between batches.”
“Drugs are getting more expensive, says Optima’s Machauer. “Companies are looking to get as much yield out of equipment as possible. The goal is to have filling equipment produce product with no rejections. With this trend many companies are looking for equipment that is smaller and slower but more effective. They want machines that are precise and as near perfect as possible. This trend also applies to the entire filling line.”
“We are seeing an increase in the number of potent products being filled aseptically," noted Walker Barrier’s Partington. “Companies are also keenly interested in faster turnaround/changeover times, and the need to decontaminate as quickly as possible. Flexibility is also a large issue as equipment is needed to be able to run various products.”n