The Needle Gets Another Shot

Contractors play a guessing game in judging lyo demand, since drugs that are developed in freeze-dried form are often later stabilized as liquids — Amgen’s Enbrel and Abbott’s Humira are two examples.

DSM is also adding capacity. “There seems to be a balance between supply and demand” in the lyo market, Novak claims. “What could throw that balance off is if a few major biologic products are approved over the next few years that exceed expectations.”

Patheon is expanding lyophilization capacity at several locations and has created a development center of excellence at its Ferentino, Italy site. Drug manufacturers are often "forced into lyophilization" because their products cannot be formulated as stable liquids formulations or sterile powders that can be filled, notes Paul Turner, Patheon's director of business development in Europe. “It chooses them.”

However, there appears to be room for niche manufacturers to compete. Consider the filling of highly viscous liquids. Hyaluron Contract Manufacturing (Burlington, Mass.) — whose name derives from its original product, hyaluronic acid — specializes in this application. Getting drugs as thick as honey into syringe barrels is no easy task, says Rebecca Butler, corporate and legal affairs manager. The company plans to increase its 34,000-square-foot facilities by another 60,000 square feet in the next few years, she says.

Special delivery

If it weren’t for newfangled delivery devices, we might not be witnessing these trends. Syringe types are nearly as diverse as the drugs they deliver: disposables and reusables, pre-filled and vial-filled, single- and multi-dose of all shapes and sizes.

Becton Dickinson continues to lead syringe manufacturing innovation, and to influence filling and packaging. BD’s Hypak SCF line is a standard bearer for the pre-filled market. The company has gradually mustered support for its Uniject, a filled pouch of plastic attached to a needle. It’s a cheap, ready-to-use yet nonreusable device that is considered ideal for vaccine delivery in the developing world (see "Safety Guides New Syringe Designs," Pharmaceutical Manufacturing, April 2005).

Fill and finish for the Uniject is a radical departure from the norm. Inova, part of the Optima Group, has pioneered equipment and processes for the product. Luciano Packaging Technologies (Somerville, N.J.) offers table-top and low-speed (120-per-minute) machines. The empty syringe reservoirs are shipped by BD in large rolls like reels of film that are fed, filled, heat-sealed and coiled up again within the filling equipment, explains Howard Leary, Luciano’s VP of engineering. The rolls are then fed into a finishing machine, which labels both sides of the pouches, cuts them into individual devices and inspects them for particulates and label accuracy.

Can Uniject make it in the major markets? Certainly, says Leary. Contraceptives and neo-natal tetanus inoculations are two possible applications, he says.

Prefilling lyophilized products

Freeze-dried product is also being pre-filled. Vetter Pharma’s (Ravensburg, Germany) Lyo-Ject dual-chamber syringe separates powder and diluent in the syringe barrel with a stopper that gives way as the patient or healthcare professional screws the device’s plunger, thus reconstituting the product. The challenge for Vetter, which fills the syringes in its contract facilities, is ensuring two aseptic fills in the same container, says Jeffrey Turns, president of U.S.-based Vetter Pharma-Turm, Inc. (Yardley, Pa.). It’s an elaborate, automated process, one that involves filling, lyophilizing and closing off the drug product in half the syringe, flipping the syringe and replacing it in a tray for liquid filling and plunger insertion on the other end. The devices are then quarantined for contaminant testing.

There are few commercialized products delivered by Lyo-ject, admits Turns, but the potential is there for high-value lyo drugs taken at home, even with multi-dose capability.

Most pharmaceutical manufacturers prefer their vial-oriented lyophilization processes, says Paproski of West Pharma. To meet this demand while giving consumers improved access to freeze-dried product, West has developed the Clip’n’Ject, a sterile syringe, pre-filled with diluent, that snaps onto a vial, allowing the patient to blend powder and diluent. “You take six to eight steps out of the normal reconstitution process,” Paproski claims.

Sterility assurance

The boom in filling technologies and capacity coincides with a tougher regulatory stance on aseptic processing, particularly from the EMEA. DSM spent three years and “a fair amount of money” to conform all of its small- and large-molecule suites to EMEA’s sterile guidelines, says Novak.

Other global suppliers wrestle with EMEA standards. Ben Venue has reconfigured its facilities to meet the EU mandate of maintaining a clear segregation of product types within the same facility. The manufacturer now has dedicated spaces for cytotoxics, genotoxics, biologics and its ethical drug products, says Henderson.

Like many manufacturers, Ben Venue has integrated wash and sterilization tunnels into its filling lines, and is pursuing more advanced barrier technologies. FDA has been all too clear that it prefers such containment systems — namely, restricted access barrier systems (RABS) or, even better, advanced isolators that prohibit operator access except through glove and RTP ports.

The dilemma is whether to take the small step to RABS or the giant leap to isolators. Ben Venue, which manufactures more than 200 products, is moving toward RABS for the flexibility it offers, Henderson says.

“Most people start by looking at isolators, but back off to RABS,” notes Jeff Jackson, director of product management and marketing for Bosch Packaging Technology, North America (Minneapolis). Manufacturers fear the validation implications of an automated decontamination cycle and not being able to open the isolator once a campaign begins.

In a way, RABS is a poor compromise, says Jackson. It requires personnel to gown up and use glove ports to operate machines. “Isolators are going to be the only way to go 10 years from now,” he predicts.

“We’re a contractor — we took a half-step [toward RABS],” says Turns of Vetter. “Traditional laminarity works,” he adds, noting that Vetter has had just one positive result in more than one million media fills.

“We haven’t decided on our final configuration,” says Novak of DSM. But, he says, “we are probably moving toward RABS.”

European manufacturers are leaning more toward isolators, says Matthias Poslovski, technical sales director for Inova and Kugler for the Optima Group Pharma.

Dispose of properly

Disposable components, popular in upstream processing, have slowly migrated downstream to aid sterile manufacturing. Tubing, valves, containers, fill nozzles and filters for filling are all available in disposable form. Millipore (Billerica, Mass.) is promoting its end-to-end, integrated disposable solutions, and will unveil a new disposable-dependent filling system at this month’s Achema 2006 show in Frankfurt.

Fill-and-finish manufacturers have been tentative to adopt disposables because they require equipment changes and thus validation work, says Millipore’s Jean-Marc Cappia, director of Mobius flexible bioprocess solutions. Cleaning validation is not an issue with sterile disposables, however, and the flexibility and speed they lend to operations have made them particularly appealing to contract fillers, Cappia says.

Patheon is embracing disposable equipment technologies, says Turner. For low-volume fills, it has invested in a new flexible filling line which includes a peristaltic pump filling system from Flexicon (Ringsted, Denmark), which compresses flexible tubing to generate fills. All product contact parts are then disposed of, and therefore no cleaning validation is required. The company's investments in this and other disposable technologies are primarily for clinical-stage manufacturing at present, says Turner. "As we take products through development, we'll want to take the advantages of these disposable technologies through to commercialization," he says.

Adding value with equipment

Equipment vendors are changing along with the times. Bosch, for example, has diversified its product line, which runs the gamut from machines based on piston pumps and rolling diaphragms to those incorporating time-pressure systems and mass-flow systems. While time-pressure systems are presently the most popular choice, says Jackson, the improved accuracy of the latest flow meters has made mass-flow-based machines a viable option. The company introduced a new line of nested fillers for the pre-filled syringe market at this year’s Interphex show in New York.

Customers are driving Bosch’s new offerings, Jackson says, and more and more that includes value-added features and solutions such as an enhanced documentation package to speed validation.

In the past, manufacturers would seek a specific line of equipment to match a given product. “Nowadays, we have to supply machines and turnkey concepts,” says Poslovski of Optima. “The goal is time to market, and manufacturers are giving up trying to be specialists.”

Contract manufacturers are also expected to provide the extras, none more important than current automation and control of operations. “Where we’re really seeing innovation is in inspection technologies,” says Ben Venue’s Henderson, whether enhanced systems for tracking particulates in liquids or clumping in lyo cakes, or weeding out faulty labels.

Automated inspection

"Automated inspection is probably the biggest part of our business now," says Leary of Luciano. The costs of vision systems and inspection technologies are down, while reliability is up, he explains, adding, "The reality is that you can’t allow any false accepts, and don’t want a high number of false rejects." Still, many applications will require a human touch. On the Uniject lines, for example, four operators are required to staff the video screens monitoring particulates within the syringe pouch, Leary says.

Bosch purchased Danish inspection equipment vendor Moller and Devicon two years ago and has since developed a full particle and cosmetic inspection system whose definitive feature is a lack of moving parts.

In-process control has also taken on added significance for sterile contract manufacturing. DSM offers control packages for liquid and freeze-dried operations. Its Lyo-Advantage, for instance, monitors 150 different critical process parameters (CPPs), and features continuous set-point monitoring, says Novak. Liquid-Advantage has similar benefits.

The Optima Group has developed in-process controls for fill volume based on high-accuracy load cells. Syringes are automatically removed 10 at a time from their nests, filled, weighed and replaced. The process not only improves on the time of manual weighing, says Poslovski, but also eliminates loss of sampled product.

Not everyone is automating everything. While many companies are switching to robotic tray loading for their lyophilization cycles, Ben Venue is one that is not. “We manufacture 2- to 200-cc vials,” says Henderson. “The changeover time and amount of parts you need for automated loading doesn’t make sense.”