Seals of Approval

March 15, 2006
At AstraZeneca’s Westborough facility, the secret to blow-fill-seal success has been developing broad expertise, and seeing implementation and operations challenges as opportunities for growth.

By Paul Thomas, Managing Editor

Blow-fill-seal (BFS) technology has steadily gained in popularity as it has matured, as single-dose packaging has become commonplace and as manufacturers place greater emphasis on aseptic processes. BFS’s most endearing attribute is its promise of advanced aseptic processing (see "What is Advanced Aseptic Processing?" Feb. 2006).

AstraZeneca has pioneered the use of BFS in Sweden, Australia and the U.S., and boasts a network of experts who exchange best practices and work towards improved consistency on a global scale. AstraZeneca starting developing BFS expertise in the 1980s, when the company bought a 10-cavity Rommelag (Edison, N.J.) machine after it had used a custom built blow-mold machine for packaging nose drops.

Westborough ramped up its BFS operations in the mid-1990s, with the commercialization of its Pulmicort Respules asthma medication — a product housed in a stylish polypropylene ampoule and inhaled by patients via a nebulizing device. There are five Pulmicort lines currently running at the facility, all using Rommelag 4010 machines, and Westborough is now regarded as the company’s blow-fill-seal center of excellence.

Building with BFS in mind

Blow-fill-seal not only gave AstraZeneca advanced aseptic processing and a class-100 rating at point of fill, but also lowered manufacturing costs and improved safety, says project engineer Mike Coyle, who has overseen the facilities’ expansion and the development of the site’s expertise in BFS operations (see Blow-Fill-Seal Best Practices, below). The growth has included a fair share of design challenges — opportunities, Coyle calls them — particularly regarding the customization of the filling equipment to meet the needs of product and process.

Foremost among these challenges was devising a means to ensure that particles of budesonide, Pulmicort’s active ingredient, are evenly distributed within each ampoule. The solution was to design and implement a recirculation loop between the machine’s compound tank and filler so that unused solution would be rerouted back to the tank and added back to the compound mix. The project required engineering support from Rommelag and a prototype to be built.

Another hurdle was devising a way to mark each respule for date, lot and code without the risk of ink leaching through the polypropylene. The original line was designed with an inkjet printer and vision system for monitoring. “The FDA was telling us, ‘Prove it won’t leach, or change it,’ “ says Coyle. They opted for change. With AstraZeneca’s technical input, Rommelag engineers affixed an embossing device onto the equipment’s de-flasher, which removes excess plastic from fill nozzles following each batch. Getting the system right took a year and a half, Coyle estimates.

Other customization projects have included separating the utility and aseptic processing sides of the equipment, providing for laminar air flow in the aseptic space, developing an aseptic means of compounding the suspension and a sophisticated aseptic piping system for the machine.

Sophisticated equipment

Each BFS machine at Westborough has 11 operational modes, among them set-up, cleaning, steaming and production. A sophisticated piping system is controlled by an equally complex valving system to ensure product purity. During commissioning, the state of the valves must be verified in conjunction with PLC and HMI settings for each operational mode.

Operator training for the equipment is exhaustive, Coyle notes. “We have a group of technicians that are trained specifically to handle mode changes on the equipment,” he says. Their education begins in the vendor factory with FAT tests, and continues with additional off- and on-site study.

Tech ops representative Mike Graika at line 2’s Rommelag punch. In the background is line 1.

Westborough has automated as much of its BFS operations as possible, though operators remain critical to the process. Separate controls systems for the compounding area and Rommelag filler indicate readiness or completion of given sequences. Operators are involved in set-up and transfer of WFI or steam from product tanks to the filling needles. Additional operator involvement can vary, depending on, for example, which tanks or transfer panels are in use at a given time, and which machines are ready to run a new batch.

A key to maintaining advanced aseptic standards with blow-fill-seal is to minimize the need for operators to enter the isolated processing space. AstraZeneca’s standard procedures and gowning requirements account for situations in which system containment must be breached — for set-up, machine repair or media fills, for example. For major problems — the breakage of a mold chain, for instance — product is aseptically reverted, under positive pressure, back to the holding tank. Following repair, Steam-in-Place (SIP) can restore the sterility of the system. Or, for extended repairs, the batch may be transferred to another machine.

Integration and de-coupling

Of the five Respules lines, the first two were installed with the construction of a new building a decade ago, a project overseen by Jacobs Engineering Group (Pasadena, Calif.). The three other lines were built as the need arose. For one, a 300-ton crane hoisted the 4010 machine over a cafeteria and through a hole carved out of a second-floor wall, Coyle recalls. This line shares its preparation area with Westborough’s parenteral facility, which required procedures, piping and schedules to be modified to support both parenteral and BFS areas.

When the first two lines at Westborough were established, they were fully integrated with secondary packaging operations. This is still true today. Product exits the filler and moves directly onto a conveying system for packaging.

With the third line, the decision was made to de-couple filling and packaging operations. The thinking was that, since the output of the packaging equipment was much faster than the blow-fill-seal machine, it made little sense to limit the use of one packaging line to one filler. And, since the BFS machines tended to be more reliable, it made little sense to risk processing backups due to packaging issues. “If you aren’t coupled to the packaging line, downtime in packaging won’t impact continued operations,” Coyle says.

For lines 3, 4 and 5, product exits the filler and is check-weighed and leak-tested, the latter using a Nikka Densok (Denver, Colo.) high-voltage pinhole detector. It is then placed on trays and pushed in hand carts to whatever secondary packaging line is scheduled at the time.

Maintaining control

Operations are controlled at both the compounding tanks and Rommelag filler. Both are connected to a qualified local area network (LAN) to satisfy 12 CFR Part 11 requirements for backup and restore.

The challenge of developing a computer validation (CV) model was made greater by the fact that FDA guidance for 21 CFR Part 11 changed just as the third line was being commissioned and validated, in 2001. Both the Rommelag HMI system and preparation process controls required validation under the CV model. And yet Westborough still met its product delivery dates for the line. “We saw the change in requirements not as a problem, but as an opportunity,” says Coyle. “It gave us a chance to reconsider and improve on what we were doing before.”

The controls systems are supported by a SCADA system that provides for alarms, warnings and messages. Westborough also maintains statistical process control for such critical parameters as fill volume, respule wall thickness and solution delivery.

Blow-Fill-Seal Best Practices

The following best practices are courtesy of Mike Coyle, project manager and blow-fill-seal expert at AstraZeneca’s Westborough, Mass., facility. For operator best practices, Coyle was assisted by technical operations representative Mike Graika.

For Installing and Commissioning a Blow-Fill-Seal Line

Best practices are those that include:

  • Conduct factory acceptance tests (FATs) that have input from QA, operations and validation professionals in order to align the overall process.

  • Perform sufficient engineering runs before formal documents are executed.

  • Get vendors involved in site acceptance testing (SATs) to ensure that reassembled equipment delivers consistently in the new environment using new utilities.

  • Perform extensive safety reviews.

  • Establish good documentation for change control.

  • Hold regular team meetings to make sure everyone is on the same page.

  • Perform regular sanity checks in order to make sure you’re doing the right thing and heading in the right direction.

For Operating a Blow-Fill-Seal Line

Best practices include:

  • Training and qualification for all operators and technicians;

  • In-depth but focused preventive maintenance procedures;

  • Continuous process improvement;

  • Good documentation for repairs and change control;

  • Constant attention to safety;

  • Thorough standard operating procedures;

  • Scheduling that allows for timely maintenance;

  • Shift overlap;

  • Coordination between production areas;

  • Equipment performance metrics such as OEE.