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- 1. 34 PHARMACEUTICAL ENGINEERING MAY/JUNE 2006 Capital Costs for Biopharm Projects Continued on page 36. This article presents cost data and analysis from several recent large process retrofit projects inside an active manufacturing plant. It also provides cost data for several types of process equipment and digital fieldbus DCS systems. It compares retrofit costs with greenfield construction costs. Capital Costs for Biopharmaceutical Process Retrofit Projects by Stephen R. Higham Introduction G enzyme’s Allston, Massachusetts, biopharmaceuticalproductionfacility is a 132,600 square foot (12,300 sq meter) building completed in 1994. It is a three story building with interstitial mez- zanines - Figure 1. Itwasoriginallyoutfittedwithmedia,buffer, cell culture, and purification capabilities for one process, as well as lyophilization and fill- finish functions. The building was constructed with two separate cell culture suites. The main (larger) suite was outfitted, started-up, and validatedin1994.Thesecondsuite(thesmaller of the two) was partially outfitted, but not completed at that time. Each suite was de- signed with dedicated gowning rooms/airlocks, inoculum prep labs, and air handlers. Starting in 2000, Genzyme embarked on a series of projects that completed the second cell culture suite, additional purification rooms, and ancillary media, buffer, and utilities ca- pacity. These projects have added 50% to the plant’s throughput, and added multi-product capability. These projects were retrofits of ex- isting space within the building, implemented while all other manufacturing processes were ongoing. Most construction cost articles do not ad- equately cover this type of project. Most articles tend to focus on greenfield construction. How- ever, in pure retrofit projects, the “bricks and mortar” are partially or totally in place, thus, greenfield estimation methods do not apply. The goal of this article is to: • provide actual cost data for various con- struction costs divisions for both cell culture and purification retrofits. • provide cost data on process equipment. • show costs for digital bus based process instrumentation and wiring. • compare retrofit costs with greenfield cost estimates from the literature. Project Descriptions For the purpose of this article, the projects can bebrokenintotwosub-projectsorphases.First, there was the build-out of the second cell cul- ture suite. This covered about 3100 square feet (290 sq meters) and involved demolishing and rebuilding two mezzanine levels. New struc- tural steel for the mezzanines was installed to accommodate the new “through the floor” tank geometries - Figure 2. The old tanks were removed, two new pro- duction bioreactors and one new seedbioreactorwereinstalled,and all were designed and purchased skidded. A process microfiltration system also was designed and purchased, as well as six cell-cul- ture process tanks ranging in size from 2500 liters to 8000 liters (660 to 2100 gallons). There was extensive field installed process and clean utility piping, both within the suite and as intercon- nections to existing processes and utilities. A new city water feed Figure 1. Genzyme’s Allston, Massachusetts facility.
- 2. 36 PHARMACEUTICAL ENGINEERING MAY/JUNE 2006 Capital Costs for Biopharm Projects and skid-mounted deionized and reverse-osmosis water sys- tems were provided as an addition to the building’s central- ized utilities, as well as a separate new Clean-In-Place (CIP) skid and CIP distribution piping. Finally, a 900 square foot (84 sq meters) renovation to the cell culture equipment prep area was undertaken. The approach taken here was to add a new glassware washer dedicated to the new process. On the clean side of the washers, the room was split into two with separate outflow paths for personnel and clean components for each process. Theotherprojectphasewasabuild-outofthreepurification coldrooms, totaling about 2900 square feet (270 sq meters). It also included creating three small formulation rooms, as well as an equipment prep room renovation similar to that de- scribedinthecellculturesectionabove.Thisprojectphasealso involved designing, purchasing, and installing purification processequipment.Thisencompassedtheuseofthecoldrooms described above, as well as several new buffer preparation rooms. The total area affected in this project phase was 6800 square feet (630 sq meters). The process equipment in the scope of this phase included a large depth filtration skid, two ultrafiltration/diafiltration systems, and five chromatography skids. In addition, 20 purification buffer and eluate pooling tanks in the range of sizes between 500 liters and 3800 liters (130 and 1000 gallons) were purchased, as well as a number of smaller portable tanks. All purification process equipment was designed for use in hazardous atmospheres, utilizing US National Electrical Code Class I, Division 2 compliant con- struction. Clean utility systems included a vapor compression WFI still, a Clean System Generator (CSG), a new CIP skid, and CIP supply and return piping. The still and CSG were needed to increase generation capacity for the new processes, and were tied into existing storage and distribution systems. Finally, a 1000 ton (3.5 MW) process chilled water centrifugal chillerwaspurchasedandinstalledtocomplementthebuilding’s existing 2000 tons (7 MW) of absorption chillers. For all of the projects considered in this article, the total affected floor space was 12,700 square feet (1182 sq meters). In these projects, space was constrained by existing build- ing conditions. This often necessitated the use of tanks with unusually high or low L/D ratios, as well as increased com- plexity and density of field-erected piping. In many cases, field piping approached the complexity and density of typical skid piping - Figure 3. In addition, skid geometry had to be carefully thought through with skids in several cases being designed in mul- tiple sections. Rigging of tanks and skids had to occur in many cases through a second floor window - Figure 4. Since the plant was in operation in adjacent spaces around the clock, there were profound schedule implications for the construction projects. Often, only small windows of time were available to take down and tie into existing utility and process systems. The same constraints were in place for Figure 2. New structural steel for mezzanine, cell culture suite. Continued on page 38. Figure 4. Tank rigging through second floor window. Figure 3. Field piping and tanks in purification buffer hold, during construction.
- 3. 38 PHARMACEUTICAL ENGINEERING MAY/JUNE 2006 Capital Costs for Biopharm Projects ConstructionDivision Division Description 2 Sitework Core drilling, demolition, temporary walls and doors, cleaning 3 Concrete Floors, equipment pads 4 Masonry 5 Metals Structural steel, permanent fall protection and retrieval equipment, decking, pipe racks, permanent metal platforms and mezzanines 7 Thermal and moisture protection Roof work, fireproofing, fire-stopping 8 Doors and windows 9 Finishes Drywalls, painting, epoxy floors, architectural detailing, suspended and drywall ceilings 10 Specialties Special architectural items 11 Equipment Rigging, storage, shipping 11a Process equipment All bioprocessing tankage and skids, not including field erected piping. All utility and clean utility equipment. 13a Coldrooms 13b Process instruments All field installed sensors and automated valves 13c Process controls Controls hardware except that provided on skids and for HVAC and building systems. All controls software, software licenses, and software development except that for HVAC and building systems. 14 Conveying systems Materials handling, forklifts, elevator repairs, dumbwaiters 15 Mechanical Fire protection systems, chillers, HVAC systems, HVAC controls, plumbing, duct insulation, utility and waste piping, safety and waste systems 16 Electrical Labor, supplies, motor controls, variable frequency drives, substations, controls and power wiring 17 Process mechanical Process piping, manual valves, non-destructive examination, insulation, passivation, turnover documentation. 18 Special conditions Includes permitting Table A. Construction divisions. Continued on page 40. Figure 5. Chromatography column cost versus diameter. access into rooms in order to do installation work. In some cases, temporary partitions were created to separate a given room into clean and construction zones. Both piping and electrical installation are more costly than in new construc- tion since work must be done behind existing walls and through cramped interstitial spaces. These types of schedule and construction constraints are easy to underestimate, and must be built into any upfront cost estimates for retrofit projects within active manufacturing plants. For all project phases, most process engineering was done in-house, including most P&ID development and equipment specification and design. Instrumentation and Control (I&C) equipment specification also was done by Genzyme engineer- ing personnel. An outside engineering company supplied piping design, structural engineering, electrical engineering, and some P&ID development. Project Costs To analyze the project costs, invoices were categorized using a modified version of Construction Specifications Institute (CSI) divisions. For the overall project’s costs analysis, cost corrections were made to third quarter, 2005 by using the Chemical Engineering Plant Cost Index. This data is presented in Table B. Note that this table presents divisional costs as both a percentage of the total direct cost for each project, as well as a cost per unit area. The cost per unit area for coldrooms uses the coldroom area, not the total project area. Equipment Costs There were two types of process equipment that were pur- chased in sufficient quantities so that cost-versus-size curves could be developed. These are chromatography columns and large process tanks. That data is presented in Figures 5 and 6. The chromatography columns are 316L stainless steel construction and are ASME pressure vessels. The tanks have 316L stainless steel wetted surfaces, 304L stainless steel insulation covers, and are ASME pressure vessels. They have internal surface finish of 20 micro-inch Ra, maximum (0.5 micron) and are electropolished. The tank cost also includes magnetic-drive bottom agitators. The cost curves are for equipment only (uninstalled). For both types of equipment, costs were corrected to third quarter, 2005. Since this equip- ment is fabricated entirely of stainless steel, a “blended cost index” was used to account for the materials escalation. The blended index consisted in equal parts of the Marshall and Swift Equipment Cost Index and the CRU Steel Price Index for stainless steel. An estimate was developed for the costs associated with typical installations of fixed process tanks. Above and beyond
- 4. 40 PHARMACEUTICAL ENGINEERING MAY/JUNE 2006 Capital Costs for Biopharm Projects Cell Culture andAssociated Projects Purification and Associated Projects % of Total Cost/Area ($/sq ft) % of Total Cost/Area ($/sq ft) DIRECT COSTS Direct Costs Direct Costs Sitework $262,043 2.4 84.5 $481,480 1.8 70.8 Concrete $43,420 0.4 14.0 $102,549 0.4 15.1 Masonry $5,333 0.0 1.7 $23,416 0.1 3.4 Metals $156,159 1.4 50.4 $1,393,740 5.1 204.9 Thermal and Moisture 0 0 0 $64,395 0.2 9.5 Protection Doors and Windows $44,615 0.4 14.4 $86,942 0.3 12.7 Finishes $319,499 3.0 103.0 $575,035 2.1 84.6 Specialties 0 0 0 $7,610 <0.1 1.1 Equipment $10,881 0.1 3.5 $447,224 1.6 65.7 Process Equipment $2,608,512 24.1 841.4 $5,385,531 19.8 791.8 Coldrooms 0 0 0 $1,179,612 4.3 406.8 Process Instruments $549,112 5.1 177.1 $1,744,982 6.4 256.6 Process Controls Hardware, $1,979,475 18.3 638.5 $3,777,121 13.9 555.4 software, software development, licenses Conveying Systems $5,441 0.1 1.8 $39,790 0.1 5.8 Mechanical $262,352 2.4 84.6 $2,513,692 9.2 370.1 Electrical $802,859 7.4 259.0 $2,742,462 10.1 403.7 Process Mechanical $3,753,836 34.7 1211 $6,620,152 24.3 974.8 Special conditions $19,192 0.2 6.2 $69,579 0.3 10.2 TOTAL DIRECT COSTS $10,811,847 100.0 3488 $27,266,192 100.0 4010 INDIRECT COSTS Engineering $896,631 8.2 $5,727,590 19.3 Construction Management $826,503 7.6 $954,339 3.5 TOTAL INDIRECT COSTS $1,723,134 $6,681,929 TOTAL COSTS $12,534,981 4043 $33,948,121 4992 Table B. Total project construction costs. the costs for the tank and agitator themselves, we have estimated that the installed cost of all instruments, valves, utility, and process piping surrounding a typical buffer or eluate tank is $160,000. For the range of tank sizes in question, this equates to a total installed cost of $2.4 to $3.2 for each dollar of tank cost. This does not include runs of pipe interconnecting a tank with the rest of the process. For transfer panels around 1-1/2" tubing OD size, costs are about $700 per nozzle and $200 per proximity switch. Control System Description and Costs Controls architecture and integration was delivered by a combination of an outside systems vendor/integrator and Genzyme I&C and automation engineering personnel. Genzyme used a new Distributed Control System (DCS) for these projects since the legacy DCS for the rest of manufac- turing was no longer fully supported, and nearing its I/O capacity limit. We also decided to standardize on digital bus technology for DCS communications with instruments and actuated valves. Foundation Fieldbus was used for most continuous-signal devices, and AS-i bus for most discrete- signal devices. Profibus DP and DeviceNet were used for certain proprietary devices or those that were not supported by the other bus technologies. For the cell culture build-out project, the DCS input/output (I/O) count was approximately 380 field I/O points, and 270 on-skid I/O points. The DCS I/O count for the purification project included 900 field installed I/O points and 330 skid I/O points. Networks using bus technologies should be more expen- sive to implement on a small scale due to increased hard- ware and cabling costs, but there should be cost savings at a certain larger scale due to the simpler wiring topology. In addition, Foundation Fieldbus presents other cost savings in electrically hazardous atmospheres due to certain intrin- sic safety aspects inherent in the design. The issue of utilizing several bus technologies, due to instrument sup- port issues, and the complications this caused with respect to explosion-proof construction, meant some initial cost uncertainties with process skids. Since identical projects were not run using both two-wire and bus technologies, a direct cost comparison cannot be made here. However, it is known that about 65% of all electrical time on the projects were spent on controls related work. This allows calcula- tions that show that the controls wiring and hardware installation cost in these projects was between $1400 to $2000 per field installed I/O point. This seems surprisingly high. Lesnik1 had DCS costs in 1996 at $200 to $300 per I/ O point. The higher cost range for the Genzyme projects can be explained by the fact that an entire new DCS infrastruc- ture was installed. The incremental costs of wiring another I/O point into an existing system would certainly be less than the cost range determined here.
- 5. MAY/JUNE 2006 PHARMACEUTICAL ENGINEERING 41 Capital Costs for Biopharm Projects Concludes on page 42. Figure 6. Stainless steel sanitary process tanks cost versus capacity. Total overall controls software and hardware implemen- tation costs were difficult to estimate in advance throughout the project. Depending on the phase of the project, Genzyme’s integrator had some or all of the following deliverables: • systems engineering and configuration • field technical service for controllers and bus • on-site operator training including hardware mockup • off-site component validation • service contract • Functional Requirement Specification (FRS) development • design and construction of system enclosures, field termi- nation boxes and I/O cabinets • software licenses and scaleups • controller hardware • controller I/O hardware • workstations • O&M manuals • project management and administration • process skids FAT support • engineering of interfaces between legacy DCS and new DCS • systems startup support Total controls hardware and software costs (minus process instruments) were in the range of 70 to 76% of process equipment costs. However, note that process skids were specified and constructed with all required instrumentation installed and wired. The skids did not have on-board control- lers, and were instead tied into the plant’s DCS system upon installation in the facility. Thus, on the costs breakdown, the instrumentation and electrical costs for the skids themselves are absorbed into the process equipment line item. Thus, while it is valid to compare controls hardware and software costs against total process equipment costs, it is a better comparison to compare instrumentation costs against only fixed tankage costs. When that is done, instrumentation costs
- 6. 42 PHARMACEUTICAL ENGINEERING MAY/JUNE 2006 Capital Costs for Biopharm Projects come in as 80% to 140% of fixed tankage costs. Future project managers would be well advised to address the costs of all these items early on in the project. However, even if the initial controls integrator project scope is well- defined, client project scope changes in both process design and project implementation can have radical cost implica- tions for controls. Other Cost Data and Literature Comparison There are other interesting facts that can be gleaned from the cost data. Metals cost for the purification build-out was several times that for the cell culture build-out. This is due to the extensive structural steel needed to install the large chiller in a penthouse. Process equipment costs were approximately $800 per square foot ($8600 per sq meter). This high number is to be expected due to the high density of the installations. By way of comparison, Pavlotsky2 estimated this parameter at $255/ sq.ft. This high density of process equipment is perhaps a hallmark of most retrofit projects. For both projects, total process mechanical costs came in at about 150% of the cost of overall process equipment and at about 540% of the cost of fixed tankage. The cost of mechanical work for the purification project was several times higher than that for the cell culture project. The purification area had several air handlers spread over a greater area, as well as the installation costs for the process chiller. The cell culture job, on the other hand, had no new air handlers, and ductwork changes were concentrated in a smaller area. Electrical costs for purification also were higher than those for cell culture. Again, this is probably due to the longer distances involved in purification, especially since all controls and power wiring had to be run in conduit. The Construction Management (CM) fees declined sub- stantiallybetweenpurificationandcellculturesinceGenzyme began to self-perform more CM tasks as time went on. Only limited information is available to compare the costs of renovations described in this article with the original building costs. The total direct construction cost of the Allston facility, converted to 2005 US dollars, was $1252/square foot. This is in contrast to the equivalent number for the new projects (including both process and utilities areas), which is $3660/square foot. The comparison is limited since the old number includes not only process and utility space, but also offices, hallways, labs, conference rooms, and the empty spaces which later were retrofitted. Table C shows more comparisons between other cost estimate work done for greenfield biopharmaceutical facili- ties and the Genzyme retrofit projects. The increased fac- tored costs for some construction divisions can be explained by the increased equipment density, smaller footprint, and the construction and scheduling constraints needed when working inside an active plant. Conclusion To summarize, certain factors contribute to driving up con- struction costs in retrofits projects. These include manufac- turing schedule constraints, rigging complications, the ne- cessity to isolate areas with temporary partitions, and to work in tight spaces behind and above finished spaces. Also contributing to costs are limits on available process space, necessitating dense skids and process installations. Finally, work is spread around the building, connecting “islands” of renovation within the building. However, these are offset by the advantages of retrofitting inside an existing manufacturing facility. These advantages include potential reduced regulatory hurdles, lower permit- ting costs, and lower “bricks and mortar” costs. In addition, some or all clean utilities are in place, trained personnel are available for start-up, validation, and operation, and existing utilities infrastructure (chilled water, electrical, waste sys- tems) can continue to be used. Actual capital cost data from retrofit projects within an active biopharmaceutical plant show dramatic differences in several respects from greenfield estimates. Capital manag- ers must be aware of these differences. It is hoped that the data and analysis presented here can be used as a guide for cost estimation for similar projects in the future. References 1. Lesnik, R., “Bulk Pharmaceuticals Manufacturing,” Phar- maceutical Engineering, November/December 1996, Vol. 16, No. 6, pp. 18-27. 2. Pavlotsky, R.V., “Approximating Facilities Costs,” CleanRooms, Vol. 18, No. 8, 2004, pp. 20-27. 3. Harrison, R.G., and P.W. Todd, S.R. Rudge, D. Petrides, BioseparationScienceandEngineering,NewYork,Oxford University Press, 2003. About the Author Stephen R. Higham is a Principal Project Engineer in the Engineering Services Group at Genzyme Corporation. He has a BS in chemical engineering from the University of NewHampshireandhasdonegraduatework in biochemical engineering. He is a Profes- sional Engineer in the state of Massachu- setts. Higham has 21 years of experience in the diagnostics, biologics, and biotechnology industries. He has held positions in project and process engineering and facilities management. He has been at Genzyme for eight years in a project engineering and capital projects manage- ment role. Genzyme Corp., 500 Soldiers Field Rd., Allston, MA 02134. Cost Item Cost Range as Multiple of Process Equipment Petrides3 Pavlotsky2 Higham (greenfield) (greenfield) (retrofit) Process piping 0.3 – 0.6 0.34 1.23 – 1.44 (assume includes utility piping) Instruments and 0.2 – 0.6 0.17 – 0.23 0.96 – 1.03 control system Electrical 0.1 – 0.2 0.14 0.31 – 0.51 Table C. Selected cost comparisons.