Fiocruz Builds Modern Multi-product Pharmaceutical Plant in Brazil for Vaccine Production

Fiocruz Builds Modern Multiproduct Pharmaceutical Plant in Brazil for Vaccine Production

Installation of State-of-the-Art Equipment and Critical Piping Systems by Orbital Welding
Barbara K. Henon, Ph.D. and Angel Brond Arc Machines, Inc.

Introduction


Fiocruz Instituto de Tecnologia em Imunobiologicos, also known as Instituto Bio-Manguinhos, a Brazilian Government Institute near Rio de Janeiro, is completing what will become the largest manufacturing center for vaccines in Latin America. This was a major construction project with the addition of a total of 15,000 m2 (161,483 ft2) in area added to their existing facililties. At a total cost of about U.S. $70 million, it will have the capability to process a total of 180 million doses per year of vaccines against yellow fever, smallpox, tuberculosis, typhoid fever, and measles. This list will be extended within the next two years to include DPT (diptheria, pertussus, and tetanus) and a vaccine for meningitis AC. The project began in 1991 and they expect to be shipping product by 1998. Fiocruz has occupied their present site since the beginning of the century when the original building, known as the Castle, was built on a hill overlooking the site by Fiocruz founder, Oswaldo Cruz. The Castle, which was constructed from materials brought from France, is an elegant building designed and furnished in a style which would be impossible to replicate in our contemporary era. Today it serves as an Administration building and is the logo and symbol for Fiocruz. Although Fiocruz has been producing vaccines since they first developed a vaccine for yellow fever, their new facility with its two new lyophilization units, each capable of delivering 45 million doses a week, will allow them to expand their operation from a purely domestic market to worldwide distribution of their products.

Quality has been a major consideration in building this facility since Bio-Manguinhos will have to comply with international standards in order to export their products to other countries. With a goal of constructing the new facililty to a standard that would meet FDA specifications in the United States, Bio-Manguinhos Director Joao Quental partnered with design engineer Fernando Avila of COBRAPI and engineering contractor, Celso Carvalho, of Termo Engenharia Ltda. (tel-termo). State-of-the-art equipment, such as multieffect stills and clean steam generators, was purchased in Europe and 3 new cleanrooms have been constructed. Some of the more critical piping systems have been constructed from electropolished 316L stainless steel and installed with automatic orbital welding. Orbital welding is the preferred method of joining stainless steel tubing for biopharmaceutical applications in the United States because the smoothness of the orbital weld compared to manual welds makes it easier to maintain the cleanliness and sterility of the piping systems which is critical to the successful production of pharmaceutical products.

New Areas


The present expansion includes the DPT building designed for production of bacterial vaccines, a new CPFI or Center for Final Processing, in which filling, lyophilization, and packaging of the final products into vials and ampules is accomplished, and utililty buidings for support of these activities which include a water treatment building, buildings for chilled water and steam generation, electrical services, and a maintenance office.

DPT - Vaccine Production Area


One important area of the DPT building is the class 100,000 fermentation room which houses the large fermentors. The fermentors are large stainless steel tanks in which antigens for the DPT vaccine will be produced.

The building environment is carefully controlled with up-to-date air handling equipment with separate air conditioning units in each area for uniform air quality throughout the process areas. While air for the lobby and offices is unfiltered, air in some rooms with process equipment is filtered twice and cooled with different units than those used for heating or cooling the offices. The floor is composed of a special polyester-based material from a Brazilian supplier and is self-leveling so that it maintains a constant surface level without collapsing. Electrical panels for servicing process equipment are located outside the fermentation area for convenient access by maintenance personnel. Even the lightbulbs have been placed in fixtures above the fermentation area so that changing them can be accomplished without introducing contaminants into the room.

In this building as well as in the CPFI, there are stations for cleaning and rinsing equipment and glassware. A crane has been installed for lifting the large transfer vessels used for transporting vaccines between buildings, and piping has been installed for delivering chilled water, DI water, WFI water at 95°C and compressed air for cleaning, rinsing, and drying. All equipment used in vaccine preparation is sterilized prior to use.

Fermentation room. Personnel entering the fermentation room are required to wear cleanroom gowns. The personnel entrance into the fermentation room is from a pressurized room by way of an air lock which locks automatically by a magnetic locking system which maintains air quality and pressure in the cleanroom. Separate transfer hatches will be used to pass equipment into and out of the fermentation room. The fermentation room has a double window from which observers on the second floor can view activities in the room. Testing and sampling of the product takes place at every step of the process to assure the quality of the finished product. At any given time, there may be one or several products in different stages of the production process.


In the new CPFI facility cleanrooms are used for packaging, QC, and final processing.

CPFI - Central Processing Facililty


Blended bulk vaccines will be transported from the DPT building to the CPFI area for filling and packaging. A final check of filled glass containers is made in an inspection room provided for that purpose. Cleanrooms are interconnected with the routing of product through the cleanrooms determined by the particular product.

Some vaccines are put into ampules in the class 10,000 cleanroom under class 100 laminar flow protection then lyophillized. Five lyophilization units will be located in this building. The time required for lyophillization varies with the individual product, but may take as long as 72 hours. After lyophilization the ampules are capped, labelled, and wrapped in aluminum foil packages.

WFI Production


USP Water for Injection (WFI) is water purified to a very high standard and at this site is used to mix with the finished product. Thus it must be pure enough to be injected into the human body without causing harm. It must be free of endotoxins and pyrogens from bacterial cell walls which could cause illness or fever in patients. One of the support buildings for the new plant is a water treatment building which takes city water and processes it into deionized water. A newly constructed water tower holds drinking water (city water) which is pumped from a reservoir to the plant. Before the water is deionized to produce DI water it is filtered through a carbon filter and sand filter to remove chlorine and minerals. It is then processed at a rate of 6 cubic meters per hour through anionic, cationic and mixed bed resins to remove ions. It goes through a second DI process and finally to a multieffect still situated in the CPFI building which produces the wfi. All connections to the multieffect still are made by orbitally welded 316L tubing.


One of the new lyophilization units installed in the cleanroom at the new Fiocruz installation.
Left photo shows side view, right photo shows door at front of unit.
The new lyophillization units have greatly enhanced Fiocruz’ production capabilties.

Water from the local water supply is collected in this tower prior to its use for the production of DI water, WFI, and steam as well as water for general purpose.

Orbital welding operators demonstrate the device they built for aligning fittings in preparation for manual tacking prior to orbital welding.

Close-up of alignment device for holding an elbow in position for manual tacking.

Piping systems in the piperack send branches for cold water, hot DI water, and compressed air to the cleaning stations in the DPT and CPFI areas.

Tubing from the piperack supplies cleaning stations with cold water, hot DI water, and compressed air.

Clean steam for sterilization. A unit supplies water for the high-efficiency boilers which each generate 3,500 kilos of steam per hour. Two boilers are in use while the third is kept as a backup system. The efficiency of the boilers is enhanced by a special unit on the boiler exhaust which reclaims heat which would otherwise be lost. Clean steam for sterilization is produced by clean steam generators.

Waste products from both the CPFI and DPT buildings is collected in tanks where any remaining live organisms are killed and the waste from fermentation and processing is mixed with sewage and the treated in a state-of-the-art aerobic digester. As a final step, solids will be aerated and retained in an outdoor pond next to the plant where Fiocruz intends to keep live fish as a demonstration of the level of waste water purity.

Orbital Welding


Piping systems. Orbital welding was specified for joining the WFI piping, as well as service piping for chilled water, air, and clean steam in both buildings. The WFI system is of 316L stainless steel. DI water for washing, hot WFI water for rinsing, and air for drying of glassware and tanks will be supplied to cleaning stations located in the DPT and CPFI buildings. Flow in these piping systems is under microprocessor control with a valve for each line controlled independently. Tubing sizes were 1/2 inch diameter with a 0.049 wall, and 1 and 1-1/2 inch diameters with wall thicknesses of 0.065 inches which is typical of pharmaceutical piping.

Weld documentation. The engineering contractor, tel-termo, has been on the site for the past 8 years working on other projects. From this time, they have used as guidelines the 3-A Sanitary Standards which were introduced in the United States by the Dairy industry in the 1950s. These standards or accepted practices were intended to provide information to installers regarding the design, materials of construction, methods of installation for equipment and piping that would assure a continuously clean hygienic environment for the production of product. On the current job, tel-termo wanted to upgrade their standards for welding to a level which would be acceptable by the fda for a comparable pharmaceutical installation in the United States. Clamp-type fittings have been replaced with orbital welding for joining the piping system. A welded system is less likely to leak, but more importantly, orbital welds have a smooth inner weld bead which is less prone to harbor bacteria than manual welds, and less apt to have crevices which might entrap bacteria or prevent thorough cleaning. Weld documentation included a welding log listing the weld number, line number, locality and date the weld was made, and the orbital welding operator ID number for each weld. In addition, similar information was typed onto a label so that when it was wet with a weak acid solution the information was etched onto the OD surface of tubing next to each weld joint. The contractor, tel-termo, which did the installation, may also be responsible for plant maintenance after the facility is on line.

Fiocruz works closely with the INCQS (Instituto National Controle Qualidade Sanitaria), which is the Brazilian equivalent of the FDA in the United States, and whose headquarters border the Fiocruz campus. The INCQS has the authority to close a production facility if the quality of the product fails to meet their standards.

Training of welding personnel. The effective use of orbital welding equipment requires that the orbital weldling operators be well-trained in its use. Training to a level where the welding operator is comfortable working with the power supply, writing weld schedules which instruct the power supply to deliver the correct amperage, RPM, time, pulsation, etc. for a successful weld on a particular size of tube or fitting, entering schedules into the machine, making and evaluating welds, takes a good two days of training, and sometimes more if translation is required or if the application is unusual. Angel Brond, Arc Machines' salesman for Latin America, trained two operators in early May of 1996. In addition to programming the power supply and setting up the weld head, they were instructed in proper purging techniques for orbital welding as well as for manual tacking. Orbital welding takes place in an enclosed weld head which is filled with an inert gas, usually argon, which protects the weld joint from oxidation as the tungsten electrode rotates around the joint to complete the weld. While the argon inside the weld head protects the outside of the weld from oxidation, the joint on the inside of the tube must also be protected.

Excessive oxidation results in discoloration or "heat tint" which is known to be associated with a loss of corrosion resistance as a result of welding and perhaps to the formation of rouge in the weld heat-affected-zone (HAZ). The HAZ is that area adjacent to the weld bead which, although it is not melted during welding, is subject to changes in grain structure and surface condition as a result of heating during the welding thermal cycle. Heat tint ranges in intensity from a pale straw color or a light bluish gray "halo" to darker browns, blues and blacks. For general pharmaceutical applications, the light straw color is usually considered to be acceptable, although more critical applications may require complete absence of discoloration. In recognition that heat tint and the accompanying loss of corrosion resistance can be prevented by purging with high-purity gas, Eng. Carlos Augusto Da Costa arranged for argon back-up gas of 99.996% purity to be supplied for this project by White Martins, a Rio-Brazil based company that belongs to the Praxair group. At that time, gas of this purity was not available in Brazil although it is now commercially available.


Orbital welding power supply from Arc Machines, Inc. with cooling unit for cooling weld head during welding. Weld
programs showing weld parameters may be printed out and used for weld documentation.

Proper purging during welding can prevent the loss of corrosion resistance, and proper purging in combination with the precisely controlled heat input of orbital welding results in a weld with little or no difference in corrosion resistance from the unwelded base metal.1,2 Tacking with a manual TIG torch is often done to align components for orbital welding. Oxidized tacks may also become corrosion initiation sites, so purging the ID of the weld joint during tacking is essential. The welders at Fiocruz made a special tool to hold the parts in position for tacking and to provide access for the argon purge.

The training went well, and by mid-summer, most of the welding for the new facility had been completed. Sanitary or hygienic welds included 24 tube-to-tube and 218 tube-to-fitting welds in the CPFI area; 6 tube-to-tube and 240 tube-to-fitting welds in the DPT area; and 26 tube-to-tube and 36 tube-to-fitting welds in the pipe rack which runs between the two buildings and connects the tubing systems in these areas for a total of 550 orbital welds. By the end of the project the total number of orbital welds completed was just over 1,000. Of these, only two welds were rejected, and this was because of an unacceptable amount of discoloration resulting from an inadequate ID purge. Although on most pharmaceutical installations there always seem to be a few welds that are not accessible to the orbital weld head and must be manually welded, on this site the piping system was designed with orbital welding in mind. By planning ahead, they were able to locate the weld joints around the equipment in such a way that all of the welds could be done orbitally.

These welds were done with a single Model 207 microprocessor-controlled power supply and a Model 9-1500 fusion weld head from Arc Machines, Inc. located in California, USA. Test coupons were done before the start of the job and at specified intervals thereafter to establish acceptable weld criteria. All welds were inspected on the OD and some were inspected on the ID with a borescope. All welds were required to be fully penetrated on the ID without excessive concavity or convexity of the weld bead, and visual evidence of oxidation was held to a minimum. There were no weld rejects. Validation of the new facility was scheduled to be done by an independent private company by the end of 1996 with the plant going into production sometime in 1997.


Fiocruz has the largest biomedical library in Latin America which helps to maintain its prominant role in the Latin American science and technology.

Project conception, funding, future plans


The Director of Bio-Manguinhos, Joao Quental, estimated that construction costs for the new facility would be about $40 million with overall costs for the total plant, including equipment and validation, climbing to about $70 milllion. Funding for the current project was through the Oswaldo Cruz Foundation which is administered by the Minister of Health of Brazil. Until now the main customers for Fiocruz' vaccines have been The State of Rio de Janeiro and the Government of Brazil. The State of Rio de Janeiro has its own distribution system with the products

being sold mainly to small laboratories in Latin America and occasionally in Africa when there was a surplus. The ability to produce in bulk quantites will give Fiocruz the potential to form partnerships in collaboration with large multinational pharmaceutical companies to produce vaccines for worldwide distribution.

If other countries become involved, this may require an international management team. Bio-Manguinhos is well situated to take advantage of these new opportunities. They have the capabililty for R&D and have the largest biomedical library in South America. They are ready to play a significant role in the expanding Latin American biopharmaceutical industry.

 


References

Kearns, J.R. and G.E. Moller. Reducing heat tint effects on the corrosion resistance of austenitic stainless alloys. Materials Selection and Design. nace, May, 1994.

Yates, D., Veldsman, W., and Warne, P. Recent developments in shielding gases for electric arc welding of stainless steel. stainless steel, July/August, 1994.

Grant, A., Henon, B.K., and Mansfeld, F. Effects of purge gas purity and chelant passivation on the corrosion resistance of orbitally welded 316L stainless steel tubing. Pharmaceutical Engineering, in press.

Hansen, J.V., Nielsen, T.S. and P. Aastrup. Root surface quality requirements- high efficiency purging or pickling? Paper 46, Conference on Duplex Stainless Steels, Glasgow, Scotland 13-16 November, 1994.