In Mary Poppins, a spoonful of sugar helped the medicine go down. Putting that medicine into a vial or syringe is a very different story. The most important rule of filling is to eliminate any risk of contamination. But against that backdrop, manufacturers, contract manufacturing organizations (CMOs) and equipment vendors must balance a number of very different needs:
User demand for friendlier delivery systems, smaller doses and less waste; manufacturer and CMO mandates for equipment that can accommodate the complexities of freeze drying for sensitive biologicals and that can be used with dispoable process equipment.
“The key factors (in filling) are product quality and safety,” says Jurgen Koch, Ph.D., managing director of Vetter Pharma-Fertigung (Ravensburg, Germany), a commercial manufacturer that specializes in producing aseptically prefilled injection systems. Ensuring sterility is essential, he says.
As a result, equipment vendors are incorporating features into their equipment, designed to reduce the risk of any contaminants entering the process. Bosch Pharma USA (Minneapolis), for instance, is selling filling units with built-in isolators and restricted access barrier systems (RABS), says Jeffrey Jackson, the company’s director of product management, pharmaceutical operations.
Isolators provide both operators and product with the greatest level of protection, enclosing the working area of the equipment completely. In contrast to the standard isolator, the RABS is not hermetically sealed, but provides an air barrier between operators and production areas. The sterile part of the enclosure can only be accessed in production through glove boxes at critical locations along the filling line. The other areas can be reached through external doors, and do not require operators to wear protective cleanroom clothing. When Vetter opened a new facility last October, it included new RABS on the filling lines, with an increased capacity of 400 million units per year.
CMOs Boost Filling Capacity
As some Big Pharma companies have been closing operations and shrinking facilities, they are outsourcing more of their filling needs. In response, CMOs have been increasing their filling capabilities. Besides Vetter, Althea Technologies, Inc. (San Diego, Calif.), a provider of contract manufacturing and testing services, has completed the initial phase of construction on its new, additional 30,000-sq.-ft. cGMP manufacturing facility. When the aseptic fill/finish wing of the plant is complete, it will include automated vial and syringe filling, inspection and labeling equipment capable of producing batch sizes of more than 100,000 units.
An employee inspects newly filled vials at Althea Technologies’ aseptic fill/finish facility.
“We are trying to grow with our clients,” says Melissa Rosness, the company’s director of contract management. “As they advance from Stage I and II to commercialization, we need to expand our filling operations.” Since many of Althea’s customers are developing biologics, this involves unique considerations.
“We can build our (filling) suites from scratch,” says Rosness. In addition, Althea already has a Drug Master File (DMF) on file with the FDA and submits annual updates, making it more cost-effective to its customer to have Althea fill the product.
Using a contractor for filling can be particularly helpful if the process involved requires lyophilization, says Audrey Butler, associate director of contract services for Ben Venue Laboratories (Bedford, Ohio). CMOs often bring extensive experience. For example, she notes, Ben Venue has over 60 years of lyophilizing experience, starting with human blood plasma for the Armed Forces. They own 21 production-scale lyophilizers, with six more on the way. One key goal is flexibility, Butler says, and the company uses a variety of chamber sizes, allowing it to accommodate requests for large batches, or to meet a client’s need for a limited raw material supply.
During lyophilization, water is removed from a temperature-sensitive or unstable product solution, transforming it into a stable, dry product with an extended shelf life, while retaining the essential properties of the original formulation. This lyophilized product can be handled and stored more easily under aseptic conditions.
Lyophilization also gives a product excellent solubility, allowing for rapid reconstitution. Heat- and moisture-sensitive compounds retain their viability. Hospitals and pharmacists prefer liquids, so lyophilized product must be reconstituted back to this form.
“In the future, freeze drying will play a greater role, since more and more highly sensitive biotech agents are being developed,” says Vetter’s managing director Koch. “These ingredients impose additional demands on aseptic production.”
The lyophilization process is influenced by the formulation and the demands of the primary packaging medium being used, he explains. It is not as simple as adding freeze drying to an existing manufacturing process.
“The know-how about freeze drying in vials cannot simply be applied 1:1 to double-chamber syringes or cartridges,” says Koch. “It is considerably more demanding and requires the appropriate filling process.”
Also affecting filling is manufacturers’ growing preference for convenient, disposable filling systems, which eliminate the need for clean-in-place and aseptic assembly of equipment, as well as cleaning validation.
Althea is using this technology and buying new equipment to fill syringes. “With disposables, there is no product contact during filling,” says Rosness. “We use peristaltic tubing and the filling needles are all disposable. Cleaning validation goes away.”