Precision vial filling

A new vial fillin

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The operation includes disposable systems and a Restricted Access Barrier System (RABS) that greatly reduces the risk of contamination. The system fills the vials, inserts rubber stoppers and applies aluminum caps. 

Vetter Managing Director Thomas Otto says, "In our Chicago facility, we focus on early-stage products from preclinical through phase II, after which we will scale up and transfer them to our commercial manufacturing facilities for phase III filling and market production. To help ensure a seamless transition to commercial manufacture, we're replicating commercial processes at our early-stage (Chicago) site." 

The Chicago facility is an expansion of Vetter Development Service. Vetter, headquartered in Ravensburg, Germany, is an independent international specialist and contract developer and manufacturer of aseptically prefilled syringe systems, cartridges and vials. It has more than 25 years of experience producing high-quality aseptically prefilled injection systems. 

The new automated production line at VDS Chicago is used to fill lyophilized or liquid products (up to 10,000 units/batch). It features an integrated monitoring system for the filling and closing process. The line can run glass containers ranging from 0.1mL to 23mL capacity.

The Restricted Access Barrier System (RABS), which is supplied by Bosch, is a rigid wall enclosure equipped with HEPA filtered unidirectional air to yield an ISO 5 classified space. All air handling equipment is built into the system and glove ports, sleeves and gloves are secured to the walls. Operators at Vetter are excluded from the RABS during normal operations. Any operator activities are performed through the glove ports. The RABS at Vetter´s Chicago site is housed in a Class 10,000 area and is itself rated as a Class 100 cleanroom. 

Vials for the operation are sterilized in an autoclave and are then conveyed onto a turntable inside the RABS. The vials leave the turntable in a single file on a conveyor and travel to a pickup point. A handling unit picks up two vials at a time and swings over and places them on load cells. 

The load cells weigh each empty vial, after which fill nozzles descend and fill the product until it reaches the set weight of product in the vial, at which point the filling stops. The precision weighing system can be programmed for different filling volumes and products, allowing for 100 percent in-process control of the amounts filled.

Disposable parts
Product is pumped from a tank into the vials by a peristaltic or a rolling-diaphragm pump. These types of pumps and the associated disposable product contact components are used to eliminate the need for cleaning validation and the long lead times for dedicated product contact components. After every product run, every piece of equipment that contacts the product is disposed of in order to ensure there is no contamination of the next product to be run.

Peristaltic and rolling-diaphragm pumps are available with PreVAS single-use sets from Bosch and so readily fit this requirement. 

The PreVAS family of aseptic single-use dosing systems is a completely pre-assembled, and pre-sterilized dosing system that is supplied with supporting validation documentation. 

This allows risk free scale up of filling operations in a single-use format. PreVAS eliminates the need for complicated cleaning procedures and validation protocols, and the entire system is quickly installed and operational in a fraction of the time that previous systems required.

Rubber stoppers are fed from a vibratory bowl and travel down a conveyor to a point where a handling unit picks up two stoppers and places them on tops of two vials, which are still in the fill zone. Rods then descend and push the stoppers tightly into place. If the filler is running lyophilized products (see below), the rods only partially seat the special lyo stoppers. 

The vial handling unit then picks up the vials and places them at another station, where a cap is applied. Like the stoppers, caps are delivered down a chute from a vibratory bowl to a point where another handling unit picks up two caps and places them on top of the stoppers on two bottles. 

The caps have aluminum skirts attached to them and the vials are next transferred to another station where they are spun against rotating horizontal wheels that come in against them and crimp the skirts tightly against the vials.
The vials discharge in parallel lanes and discharge onto a right angle take-away conveyor. 

Lyophilization
Some products require lyophiliza¬tion, which is another term for freeze drying. Freeze-drying is a method of choice to remove the liquid reactant to support stability. Freeze-dried products will typically have a longer shelf-life than liquid compounds. 

Freeze-drying works by freezing the compound and then reducing the surrounding pressure to allow the frozen water in the material to sublimate directly from the solid phase to the gas phase. It is typically used to dry heat-sensitive products, because no heat is applied to the product being dried. 

At Vetter, vials are diverted out of the filling line after the lyo stoppers have been partially inserted. To evacuate water vapor, lyo stoppers have channels in their sides through which the water vapor can discharge. In addition, the stoppers are not pushed completely into the vials.

The vials are pushed onto an enclosed platform mounted on the side of the RABS. When it is filled, the operator pulls the accumulated vials onto a tray, which he inserts into the lyophilizer. The unit at Vetter, which was supplied by Hof Sonderanlagenbau GmbH, can accommodate 10 trays on five levels. 

After two trays have been inserted side-by-side on the first level, the unit automatically raises them so two more trays can be inserted on the next level. This operation is repeated until all 10 trays are inserted, after which the unit is closed and vacuum is applied to the chamber. 

It typically takes about one to four days (depending on formulation and fill volume) to complete the lyophilization, which yields a solid layer of product in each vial called a lyo cake.

The vials containing the lyo cake are placed back on the infeed turntable and enter the line. The vials bypass the filling and stopper insertion steps, and the operation resumes at the point where rods descend to push the stoppers into the vials. 

Otto says, "Vetter is the first company to use the new Bosch system, designed specifically for clinical-stage, high-value pharmaceuticals. The Bosch filler uses all disposable drug-contact components, which eliminates the need for cleaning validation and thus saves valuable time and costs."

Otto continues, "It is a compact machine with minimum tubing lengths for increased API [active pharmaceutical ingredient] yield, which is especially important for the high value products Vetter manufacturers for its customers. One liter of API could easily be valued at over $1 million and be the result of several years of effort by a biopharmaceutical development team. And the machine includes a 100 percent check-weight system. That's important, because if the amount of drug in a vial is inaccurate, that may affect the outcome of a clinical study, especially in small, early-stage trials." 

Extensive automation
Vetter's production line has elevated clinical manufacturing and development to a new level. The MHI 2020B allows for self-monitoring and self-controlled filling. The extensive degree of automation enables a high level of safety of the filled drug substances. The line also has automatic processes for transportation and in-process controls as well as filling and closing. 

Vials are filled with high precision and are closed in conditions that meet the highest possible cleanroom classification standards. This increases the protection for both the drug substances and for the participants in the clinical tests, an important contribution towards the successful completion of the early drug development phases. Rapid and flexible use of various disposable systems permits Vetter to efficiently adjust the manufacturing process to the requirements of the respective drug substance. 

Clinical development of new drugs is a key challenge for the international pharmaceutical and biotech industry. Ever-increasing competition and the pressure for innovation-combined with high development costs, government regulations of quality and safety-all require new solutions. 

Therefore, efficiency combined with high international standards and optimal time-to-market is critical. Often, candidate drug substances are produced in complex laboratory processes and are only available in limited quantities. In addition, many drug substances are complex compounds that are extremely sensitive to environmental influences.

Vetter´s vial-manufacturing line in Chicago provides a solution to the economic and technical requirements of clinical development. The facility can run small-scale fillings for testing during preclinical to phase II stages with greater efficiency and safety. 

The modular use of disposable filling system kits allows for faster and safer preparations for each fill and also reduces complexity and costs during the preparatory period. Small-scale fillings for development studies (compatibility, informal stability tests) can be realized on the line. Using tubes and pumping systems that are particularly gentle on the product, as well as automation of the product from start to end, enables Vetter to obtain especially high process yield. 

Fewer sample removals, avoiding destructive in-process control (IPC) testing and reduced loss in the tubing, all assist in a considerable reduction in the loss of active drug substance. 

The production line meets high international standards, contributing to higher yields of available amount of drug substance candidates and saving valuable time and money.

In addition to the automated vial line, the 24,000-sq-ft Chicago facility includes a second cleanroom for semi-automatic filling of a variety of drug-delivery systems, as well as chemical analysis lab, microbiology lab, material preparation and compounding functions, visual inspection, cGMP storage area and administrative offices.
Overall, the site allows the company to offer a range of services revolving around the clinical development of parenteral drugs, supporting customers from preclinical development to phase II. 

For phase III and commercial manufacturing, the Chicago facility provides seamless product transfer to Vetter's large-scale manufacturing facilities in Europe.

Bosch Packaging Technology Inc., 763-424-4700. www.boschpackaging.com
Hof Sonderanlagenbau GmbH, +49 6462-6080. www.hof-sonderanlagen.de