Glaxo Wellcome`s innovative approaches prevent cross-contamination
A unique combination of facility design, automated storage and retrieval systems (ASRS) and MMI (Man-Machine Interface) help Glaxo`s Canadian facility provide 24-hour manufacturing and packaging of over 100 products.
By Susan English-Seaton
Engineers at Glaxo Wellcome (Mississauga, Ontario) designed several solutions aimed at preventing cross-contamination into the company`s new $87.19-million technical center,
which officially opened in June. The unique layout of the six-story, 228,000 sq. ft. facility includes a $36.33-million pilot plant and analytical and development labs for its Pharmaceutical Science Division, and is geared to the ultimate in contamination control in manufacturing and production. Production lines are aligned with an automated storage and retrieval system (ASRS), which quickly conveys raw materials from a centrally located warehouse via airlocks directly to clean manufacturing and packaging areas.
Design solutions
A myriad of solutions for preventing cross-contamination have been designed into the Glaxo Wellcome facility. The entire manufacturing operation is controlled by an integrated software system. Operations are performed in Class 100 to 1,000 air at point of supply. PLCs (programmable logic controllers) control environmental conditions in each of the rooms, functioning as individual air-handling systems. Personnel can control and communicate with variable air volume systems. They can also reserve a work space and pre-program it for temperature, pressure, humidity and air exchange rate, a procedure known as “booking a room.”
According to Glaxo Wellcome Design Manager Phil Hyland, no modular cleanrooms were used because of concerns about bacterial contamination. “Most of those systems still tend to have seams at the floor and where the walls join, which are very difficult to clean effectively. So from a microbial viewpoint, they`re difficult to justify on this side of the industry.” All corners in the Glaxo Wellcome facility are 2- to 3-in. coved, he adds. Elastomeric paint is used on walls, and floors are sheet vinyl or static-dissipative epoxy where alcohol and solvents are handled.
Commissioning and validation
An extension of the company`s Canadian headquarters, opened in April 1992, the facility combines product development and manufacturing in the same building, taking a drug from early development through clinical trials to full manufacturing. Its first product out, Rotacaps — a delivery form for asthma medication — was sold in March 1997, with first approvals from the Canadian Health Protection Branch (HPB) in June. FDA approval is expected shortly.
Because Glaxo Wellcome manufactures products for the U.S., as well as domestic and international markets, it is governed by FDA GMPs and other regulations and subject to inspections by the FDA and the Canadian equivalent, the HPB. Hyland says system startup is governed by a formal protocol which must be pre-approved by the project team, the engineering team, and quality assurance groups. With approved acceptance criteria, every damper — every portion of a system — is tested against peer-approved criteria, which then has to be formally signed off as an acceptance.
“Effectively, from an FDA and HPB regulatory authority standpoint, you have to start up the HVAC system as though you were in an ISO 9000 environment,” Hyland says. “You check everything against formal criteria — pass or fail. It`s an extremely formal and well-documented commissioning process, so that at the end of the day, you know exactly what you`ve got, not what the designers say you have.”
Building control systems
For Glaxo Wellcome, an open client/server system, integrating all systems within the building, including environmental controls, was a key objective. Other goals were to automate routine operations, standardize production processes, provide user-friendly interfaces, and maintain flexibility for future growth. The technology chosen was from Modicon (Toronto) for its scalable architecture and the ability to communicate with the facility`s computer integrated manufacturing system. For the environmental controls, TAVA Technologies/ACS (West Chester, PA) chose Modicon`s PLCs. Initially, compact units were used, but as the system grew in size and sophistication to more than 2,000 I/O points, higher capacity units were introduced. The PLCs and workstations were networked by Modicon`s Modbus.
Using commercially available instrumentation, the All-Control Systems business unit of TAVA Technologies provided an individual PLC dedicated to each of 29 air handlers to meet the demands on the building`s HVAC system. The PLCs are networked to three SCADA (Supervisory Control and Data Acquisition) nodes — PC workstations located conveniently around the building for the operating staff.
Thanks to the Point Manager Concept, which delivers material right to point-of-use packaging lines — cleanrooms located in parallel to the central warehouse aisle — secondary material handling has been eliminated. The ASRS includes a warehouse 378 feet long ¥ 90 feet high ¥ 16.5 feet wide. Two high-speed, unmanned cranes pick up and deliver materials directly to their point-of-use through 73 automated doors, guarded by airlocks, located throughout the building. In parallel are the primary and secondary rooms — all cleanrooms — paired with change rooms. In primary rooms, solid dose or liquid material is placed in a container, foil, blister or bottle. It is then packed into a carton, labeled, and placed on a skid in the secondary room.
The facility
Phase One of the project was construction of the first three floors of the technical operations facility, used mainly for the packaging of bulk material, ointments, tablets, capsules, gel-caps, bottling lines, office spaces, and QA/QC labs. Phase Two encompassed the three remaining floors — the pharmaceutical sciences section, consisting of laboratories, a pilot plant, offices, containment suites — and additional QA/QC laboratories. Phase Three, now under construction, is a $3.63 million production facility for manufacturing two new products — Mepron and Malarone — scheduled to be commissioned by the end of the year.
In addition to the usual cleanroom apparel, local protective devices are worn, depending on the potency of the product. Cleanrooms are interspersed with gowning rooms on all floors except Level 3, a mechanical service space where the majority of the air handlers are located. Level 2 consists of twelve cleanrooms, which are manufacturing space, and five primary packaging rooms. Each primary packaging room has a secondary packaging room running on non-HEPA-filtered air. A block of rooms for solid dose manufacturing contains a Rotacaps room, three compression cubicles, two pan coaters, and a granulation suite.
The remainder of the floor is laboratory space. Level 4 has 15 cleanrooms: a dispensary booth and a large area for development labs, a pilot plant consisting of ten clean areas separated by dividers, and a dispensary area for the solid dose area — one large room with two dispensary booths. In the liquids area, there is a manufacturing and a primary packaging room. On Level 4, in a space approximately 60 yards long ¥ 9 yards wide, where solvents and other extremely potent materials are handled, the decision was made not to recirculate the air but to supply 100 percent fresh air. For pure energy savings, says Hyland, the space also has the ability to operate at 50 percent capacity airflow, and individual areas can be switched to low airflow.
The facility`s water generation plant is a reverse osmosis water system with continuous deionization via electrodeionization, with a water softener in front. It feeds three individual water systems: a processed water loop system, a humidification loop system, and a laboratory water system. The process loop consists of three loops distributed throughout the building. For the humidification and process water loop tank, storage tanks are continuously ozonated. UV is used to destroy the ozone, then the water is circulated throughout the building.
The HVAC system
The handling of hazardous materials, as well as powders, makes rigorous demands on the building`s HVAC system. “Where product is exposed, all exhaust air is HEPA filtered,” Hyland says. “With our products, we`ve got two concerns: the first is that the air supplied to the space is clean and free of particulate. The second is safety. Because we`re dealing with potentially very potent compounds, we want to know that someone in the mechanical space can open a duct and feel safe.”
Containment rooms, primary packaging, manufacturing, and pilot plant areas, as well as product and development labs, are all controlled environments, but only the air at point-of-supply is classified per Fed-Std 209E. Typically, cleanroom air particulate limit is 10,000 to 0.5 micron at point of supply, which is equivalent to about Class 100. “We`re probably in the range of Class 100 to Class 1,000 — that`s without ceiling-mounted HEPA filters,” Hyland says. Rooms are kept at an average temperature of between 20 and 21 degrees C at 35 percent relative humidity. In one area, where development takes place, says Hyland, there is a subsidiary air handler capable of running suites down to 20 percent rH, if required.
Unlike a traditional cleanroom, where airflow cascades from cleanest to dirtiest, positive-pressured airlocks keep powders under control. “We`re relying on positive pressured airlocks throughout the building to keep the powders from flying around and prevent cross-contamination,” says Hyland. “In practice, the cleanroom is isolated from dirty areas by positive airlocks vs. a straight cascade. At times, we use air curtains as well, because we don`t want to contaminate the cleanroom; but equally so, we don`t want any particulate to escape into the general open areas in the building. So it`s a double concern.”
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Glaxo Wellcome`s technical center in Mississauga, Ontario, houses manufacturing and the Pharmaceutical Science Division.
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In the solid dose manufacturing area, operations such as tablet press require close control of relative humidity.
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A fluid-bed dryer being loaded with granulations for compression tablets.