Because pharmaceutical filling bridges the huge gap between bulk manufacture and distribution, every link in the pharmaceutical supply chain contributes to how a drug is dispensed into a saleable container. Whether a drug is sold in single- or multiple-dose format; whether it's administered to one patient or to several or by the patient himself; whether it's split up at a pharmacy "all determine whether a filling line dispenses microliters or liters, single tablets or lots of 500 capsules.
Speed and cost-cutting, recurring themes in filling, impart the flavor of smart inventorying and just-in-time manufacture. Even pharmacology, pharmacokinetics, and active ingredients' chemical structures influence how drug packages are filled.
Packaging should be designed with filling in mind, but packaging and filling experts are not always on the same wavelength. "You'd be amazed at how many programs we enter at the eleventh hour," says Howard Thau, President of Westwood, N.J.-based Sonic Packaging, "where creative packaging designers have proposed a design that can't be filled, or where packages are so expensive to fill that the labor costs more than the drug."
The desire for better safety, compliance and convenience "often at the cost of higher unit pricing" is propelling unit-dose (single-dose) packaging, particularly prefilled syringes and blisterpacks, both specialties of Sonic's. Unit-dose packages, like metered-dose inhalers and to-deliver droppers, present unique problems for liquid and solid-dose filling, respectively. "On a per-dose basis it's always more expensive to produce unit-dose packages," Thau comments.
With some very high-value medications, however, unit-dose syringes can actually be more cost effective than multi-dose preparations, says Jeff Turns, senior vice president for Vetter, a Yardley, Pa., firm that specializes in aseptically filled, self-administered, prefilled single-use syringes and multiple injection devices.
"The 15% to 20% of injectible solutions that are wasted in each multi-dose vial can be worth hundreds of dollars," Turns explains, "which is significantly more than the cost of five or ten vials." Plus compliance, in the long run, can save on overall healthcare costs by reducing the need for more costly interventions. Turns' numbers are verified by Fred McMillan of West Pharmaceuticals, Lionville, Pa., who says that vials for injectible drugs are typically overfilled "by ten to twenty percent" to compensate for waste.
These innovative packages, which necessitate equally novel filling methods, are driven by convenience and dose accuracy. Prefilled syringes are not just for injectibles, adds Marian Robinson, vice president at Baxa, Englewood, Colo., pointing out that syringes are making inroads into oral medications as well.
Sterile Liquids Rule
Manufacturers of tablets and capsules may argue otherwise, but by far the highest value-added filling operation is sterile liquid fill because of the operation's technical difficulty and dire consequences for failure.
Maintaining a clinical fill operation is expensive and requires specialized skills that are only intermittently used. Large pharmaceutical companies therefore tend to farm out sterile fill for development and clinical runs, if not for all their sterile filling needs.
Sterile liquid fill comes in two flavors: aseptic and terminally sterilized, but complex drug structures and formulations are slowly killing terminal sterilization. "These days, fewer and fewer drugs, and no biotech products, are filled that way," observes Tom Thorpe, president of Afton Scientific, Charlottesville, Va. Another reason for outsourcing, says Thorpe, is that " surprise! " in research-driven companies R&D and manufacturing types don't always get along.
"Complex, expensive, aseptic pharmaceuticals are the most likely to sent out to contractors for filling," says Glenn Restivo, life sciences manager at Rockwell Automation, Philadelphia, Pa. "Research-oriented pharmaceutical companies tend to view manufacturing as a necessary evil, and packaging, especially, as a cost center, so they farm it out."
Sterile filling requires dedication and expertise that are often best delegated to specialty fillers. "Good design, good discipline, practice, and training are the keys," Thorpe says.
Because verifying sterility without destroying product is impossible, fillers rely on good records and simulation of their process using vials or syringes filled with microbial growth media. Still, both systematic and nonsystematic errors creep in. So during training, filling line operators are subjected to all manner of intervention scenarios, for example retrieving a stopper or broken vial from a relatively inaccessible part of the machine, starting and stopping a line, and fixing a machine malfunction. These should be rehearsed and repeated, says Thorpe, until workers' technique is perfected.
As a filler of small-scale commercial products and clinical trial doses, Afton understands its position within this marketplace, according to Thorpe. "It's very difficult for fillers that do very large runs to do small runs. Since cost and operating structures are different for very large and very small runs, it may not be economical for filler or customer." Because one size won't fit all, Afton's customers tend to be smaller biotech companies, universities, government agencies, and larger firms with immediate need for finished, small clinical batches.
A larger contract filler, Thorpe explains, will consider taking on a small job for an established customer with whom they have significant other business. "But if it's for a one-off biotech with no history, large fillers balk because only 19% of Phase I drugs make it."
Exciting new wrinkles to aseptic filling include blow seal (for larger bottles) and form seal (unit- or several-dose) filling. Both extrude polyethylene resin into a mold, fill the cavity aseptically, and punch out finished product.
An isolator system or Class-100 cleanroom is typically required when sterile-filling ampoules; either option must be integrated with space for vial sterilization and storage. Caps, septa and seals are handled and stored separately. "Stopper washers alone can cost $1 million and require a long validation cycle," points out Ray Joske, senior vice president for Dey L.P., Napa, Calif. Because each vial undergoes several operations, classified processing areas (or isolators) tend to be large. Form/blow filling uses a relatively tiny two-by-one-foot class 100 stainless steel "air shower."
Blow/form seal greatly reduces sterile filling complexity but manufacturers are skittish about subjecting most products to extrusion temperatures, limiting (in the U.S.) this type of filling to ophthalmic and respiratory products. Joske believes that's a shame. In Europe, fillers routinely use extruded polypropylene to house injectible drugs as well as the more common eye and lung treatments. Some European packagers add luer ports or septa, transforming their creations into multi-dose packages. Joske also sees the trend toward developing inhaled dosage forms of pill- and liquid-based medications as a strong signal for blow/form containers.
Anke Henke of Rommelag USA believes the United States lags behind Europe in the new plastics revolution because of inertia, familiarity with glass containers, and aversion to validation for newer blow fill lines. But sooner or later, she expects a big breakthrough for polymeric drug containers. "Plastics have many advantages compared with glass, including easier handling and transportation, and lower breakage," she says.
Although Henke admits that "very temperature-sensitive" drugs probably cannot be blow-filled, she feels that writing off proteins and other labile products is a mistake. Because blow-filling is so rapid, product is heated only transiently and quickly cooled. "Product can even be frozen immediately after leaving the mold," she notes.
Watch for Freeze-Drying
If necessity is the mother of invention, lyophilization has engendered more filling innovations than any other dose strategy. The process confers added stability and shelf life to peptides and proteins, and many (relatively) small organics like macrolide antibiotics. Lyophilization began gaining steam during the 1970s and 1980s, when pharmaceutical products were principally small molecules " with an occasional vaccine " in simple formulations. Today, with so many biotech products coming into production, lyophilization's star appears to be rising.
The bad news is that lyophilization vials spend a lot of time between sterilization and final seal. By contrast, liquid-dose sterile-filled vials remain in classified areas or within an isolator only long enough to be capped. The entire lyophilized batch " drug, vial, and sometimes seals " must be kept in a clean environment for many hours, sometimes days. Obviously that area is off-limits to unprotected human contact, and must be kept punctiliously sterilize for the duration. Monitoring and validating this level of cleanliness is expensive.
Fifteen years ago, standard lyophilization lines processed between 50,000 and 60,000 10-ml vials and cost about $1 million. Today, 100,000-vial lyophilizers are not unusual and their cost has risen to upwards of $2 million. With the added cost comes sophisticated features like high throughput, automated transfer and loading, and of course automated filling with the usual level- or mass-detecting bells and whistles.
If lyophilization confers so many benefits, why isn't it used more? Principally because of cost. "Lyophilization is so much more sophisticated than liquid ready-to-use preparations," says Ed Trappler, president of Lyophilization Technology, Ivyland, Pa. Before taking on a lyophilization project, Trappler makes sure the sponsor knows what they are getting into. "Freeze-drying cycles can be as long as 13 days, and if something goes wrong with equipment during that time you lose the batch. Plus capital investment is high, and there are even costs associated with end use, for example reconstitution buffers and labor." All of which impacts unit cost, which for the foreseeable future rules pharmaland. According to Trappler, lyophilization adds so significantly to unit cost that some companies have put considerable effort into switching from a lyophilized form to solution.
Isolators " the Future?
Pharmaceutical engineers enjoy debating the relative merits of isolators and cleanrooms. But isolators " although they're installed in less than 30% of facilities " are clearly winning on the sterile filling front. James Agalloco, president of consultancy Agalloco and Associates, Belle Mead, N.J., puts it more bluntly: "Isolators represent the future of aseptic filling."
Forward-looking manufacturers fit new filling lines with isolators, rather than installing lines inside cleanrooms. Benefits of isolators include easier maintenance of classified-grade space, lower cleaning (and potentially lower cleaning validation) burden, much lower operating costs (gases, floor space, utilities, monitors), happier operators (no gowning, claustrophobia), and optimal protection of operator from drug and drug from operator.
Isolator designs vary as much as fill-line layouts, but typically vials are fed through a tunnel and come out through a "mousehole." Stoppers and smaller components enter the enclosure through one of several rapid transfer ports, and of course repairs/maintenance are conducted through glove ports. Companies like Bosch and IMA supply filling machinery within isolators or isolator-enabled. "Or you can shop around for each component, mix and match," Agalloco observes.
Isolators do have drawbacks, though. Complex machines and processes are difficult to manipulate and maintain inside an enclosure through glove ports. "No doubt isolator systems can slow you down, or make difficult processes more so," notes Agalloco. For example getting a tool into an isolator in mid-process takes time. Isolator systems demand foresight, planning and consideration of potential failures to make them work. "If a vial falls inside a cleanroom you kick it into a corner and pick it up at the end of your shift," says Agalloco. "If enough vials get misplaced inside an isolator they can get in the way of normal operation."
The consensus among manufacturers is that isolators cost about as much as a cleanroom. And while operating costs are lower for the smaller chambers, isolator validation is more complex, and takes much longer than for a cleanroom.
According to Ed Trappler of Lyophilization Technology, isolators also are gaining traction in lyophilization facilities, especially as retrofits to lines formerly housed in a cleanroom. "But my personal opinion is the verdict is still out on isolators in freeze-drying because the lead times are so long for installation." Fitting cumbersome lyophilization equipment with an isolator system can easily add half a year to the eighteen months it takes to install such a system in a classified space.
According to John Erdner, president, of IMA North America, Bristol, Pa., competing in the filling machinery marketplace is difficult without constantly innovating. While relatively few customers use IMA's machines with isolators, end-users are increasingly demanding that capability despite the added set-up and validation costs compared with cleanroom installations. And although not exactly endorsing it, the FDA appears intrigued by the idea and has provided a gentle nudge in favor of this trend.