Contract Manufacturing / Aseptic Processing

A Tough Order to Fill

Expensive and fragile biologics, longer shelf-life and storage requirements and user-friendly demands are shaping the filling process.

By Bill Swichtenberg, Senior Editor

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.

Freeze Drying

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.”

Disposable Filling

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.”

Disposable filling is particularly beneficial for cytotoxic products., since  it eliminates the need for operators to handle the product, enhancing both product sterility and worker protection. The process also works with products that cannot have metallic contact.

Metal interactions are becoming an issue for process equipment. Jackson notes that Bosch has begun replacing stainless steel parts with plastic parts on some machines. “Drug companies are evaluating their products for interactions or effects that steel may have on the end-product,” he says.

Disposable filling systems are gaining popularity because they save time and production costs, especially for biologic drugs. Previously, when a company processed biologics, it had to purchase filters, tubes, valves and storage containers from multiple vendors. Before production even began, plant personnel had to spend time assembling, sterilizing and validating those components. Disposables eliminate most of those steps.

“Companies are trying to get away from stainless-steel vessels,” Rosness says. “Bags are more user-friendly. You start anew for each product.”

Prefilled Syringes

Growing demand for patient-friendly delivery forms has also increased interest in aseptic prefilled systems. “Prefilled syringes provide one less step that healthcare professionals or end users need to take,” says Ben Venue’s Butler.

In addition, they reduce the risk of misidentification, dosage error and contamination. For pharmaceutical companies, they eliminate container overfill that can be associated with vials. This is important when the product is in short supply, such as a vaccine.

Switching to a prefilled syringe presents its own set of challenges for manufacturers. In a prefilled syringe, a drug comes into contact with materials it does not encounter in a vial. For example, lubrication is of limited importance in a stopper for a vial. In syringes, however, lubricity is essential to proper functioning of the device. The plunger must move smoothly and easily. Silicone is often used to ensure lubricity. Determining how silicone will interact with a given drug’s stability and aggregation is a problem for both formulators and fillers.

“Modern filling lines must react with much greater flexibility to this development in terms of formats and systems,” says Koch. Vetter has used baked silicone to reduce the amount of free silicone in application systems. When exposed to hot air, the silicone binds to the glass barrel of the syringe, preventing the injection of silicone along with the drug.

Bosch has tweaked its equipment to handle syringe filling. One line can fill and seal up to 30,000 syringes an hour. The system features an automatic in-line weight inspection and integrated isolator, which results in a smaller footprint without compromising process security.

“Multi-dose containers are quickly going away,” Jackson says. “Smaller batches and individual doses are what we are seeing,” pointing to user’s requirements to reduce waste and speed up production.

Althea’s Rosness points to increased demand for dual-chamber syringes  designed for biological formulations. A drug can be lyophilized and packaged with its diluent, reducing the amount of overfill from two vials.

“It’s just easier on the clinical side,” says Rosness. “There is no pulling the product out and mixing.”

 

Smarter, Safer Filling

Manufacturers of filling equipment are emphasizing process safety and control and sterility assurance in their latest offerings.  Here are some recent examples:

BFS - With a variety of drug products comes a variety of filling methods. Blow/fill/seal (BFS) technology combines the formation of the container, its filling with a liquid drug or biologic product, and the formation and application of a seal for the container, all in one compact, automated machine. The aseptic process allows for continuous operation without exposing the product to non-sterile environments between process steps.

The blow/fill/seal process offers the flexibility of plastic packaging and is ideal for unit-dose design. Unicep Packaging Inc. (Sandpoint, Idaho) uses a modified BFS system that limits the heat and dwell exposure, therefore allowing flexibility in the volatility and viscosity of the packaged products. Their newest product, available in late 2007, is a single-use wand applicator integrated into the Twist-Tip unit-dose vial designed for topical applications. A variety of applicator choices allows liquid, cream, lotion or gel products to be administered topically through custom shapes, colors and sizes.

Process Control and PAT - Incorporating process control features in filling equipment is another area being explored. Intellitech, Inc.’s (Westminster, Md.) intelliFiller SFS (syringe filling system), introduced in February, accommodates a range of syringe sizes and fill volumes at speeds up to 150 units per minute. This system facilitates process understanding in a Process Analtyical Technology framework. The machine provides in-line process measurement, electronic recordkeeping and controlled operator access. Remote process monitoring and control is possible through secure network access. Intelligent machine controls enable the download or upload of process data.

Waste Minimization - Since the cost to manufacture many biotech products is high, it is important to use all of the drug in the filling process. Inova Pharma Systems (Schwäbisch Hall, Germany) has developed a filling and closing system for nested prefilled syringes that allows automated, sterile, in-process control. Combining a weighing system with the unit provides a fully automatic, non-destructive control capability. Automating the weighing process means samples are taken on-line without having to destroy the product after inspection. In addition, a self-optimization feature offers results that serve as calibration feedback for the dosing station, further reducing product losses.

Disposable Assembly - Concerns about cross-contamination during filling are eliminated by the new disposable aseptic fluid path (DAFPA) assembly system made by Flexicon America (Burlington, Vt.). In the DAPFA system, the bag, filter, tubing and filling needle are pre-assembled, double-bagged and gamma-irradiated. Contamination is prevented because after each production batch, the entire fluid path is removed and a new one is used. This reduces set-up time and cleaning validation.

For Bio, No Mixing or Free Silicone - Prefilled syringe manufacturer BD (Franklin Lakes, N.J.) offers the Readyfill, designed for biologicals and other sensitive drugs. The injection liquid is completely isolated between elastomeric stoppers for storage. No mixing or reconstitution necessary. Two of its advanced features are needle isolation and the use of baked silicone. Needle isolation ensures that drugs sensitive to needle contact are not affected during storage. Binding the silicone to the glass barrel through a proprietary technology reduces the level of free silicone for silicone-sensitive drugs.

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