I
’
?-
c”
development and commercialization of the quadrupole mass spectrometer (QMS) started in the early 1960s and had a major impact on the growth and breadth of the MS field. When the QMS was introduced as a commercialanalytical instrument in the mid- to late 1960s, MS was being used principally in research laboratories of academic institutions and petrochemical companies;such operations normally required the services of full-time, highly qualified mass spectrometrists. It is estimated that the worldwide annual sales of mass spectrometers amounted to some $20-30 million in 1967, with magnetic sector instruments accounting for most of these sales. The QMS, most often used in a GC/MS system, brought about dramatic growth in the ensuing decades, establishing MS as the third largest analytical instrument market (after LC and GC) by the late 1980s. Currently the worldwide MS market is estimated at $750 million, with quadrupole MS (including quadrupole ion trap MS) accounting for more than 75%of this total.
Robert E. Finnigan Consultant, Thermo Instrument Systems 0003 -2700/94/0366-969A/$04.50/0 0 1994 American Chemical Society
The advent of the quadrupole mass spectrometer helped to establish MS as an important technique for organic analysis
techniques that the operator may not even realize the instrument includes a mass spectrometer. We can already see this trend in some recent commercial products. In this Report I will provide a history of the QMS: its beginnings, its early develop ment and commercialization,and how it helped to establish MS as a broadly accepted analytical technique for organic analysis. The beginning
The QMS was invented by Wolfgang Paul Many believe that MS, including hyphenof the University of Bonn in the early ated techniques such as GC/MS and LC/ 1950s. He published his original work in MS, will become the largest segment of 1954 and applied for patents at approxithe analytical instrument market by the mately the same time. Unfortunately,his year 2000. U.S. patent applicationwas filed more than The development of MS is further illus- a year after his initial publication and trated by its integration with separation therefore was invalidated; the patent was techniques: It is becoming difficult to dis- never tested. It was not until many years tinguish markets such as chromatography later (1989) that Paul was recognized from MS. MS was once considered a spe- with the Nobel ‘Prizefor his quadrupole as cialized method requiring complex, so- well as his ion trap work. phisticated analysis by highly skilled sciAlso in the early 1950s, Richard Post of entists; it is rapidly becoming a ubiquitous the University of California Lawrence Bertool in analytical labs. Currently, most ankeley Laboratory carried out research alytical chemists use MS in a wide range of work on the QMS, independently of Paul. applications. In the future, many MS sysHe neither published nor applied for a tems will be so fully integrated with other patent. The only record of his work is a Analytical Chemistry, Vol. 66, No. 19, October 1, 1994 969 A
tomers in late 1963, and most became customers of EAI. We formally introduced the Quad 200 RGA in early 1W for use by physicists, physical chemists, and space scientists. It was an immediate hit. Initially, we set the price at $8500, but we continued to increase the price until it reached approximately $14,000, with orders increasing rather dramatically the entire time. The only competition then was the Bendix time-of-flight mass spectromeared quickly from the that most RGA users found the QMS provided superior daytoday performance (particularly in sensitivity) for less money. From the beginning, the QMS was a forgiving instrument; it produced a usable spectrum even when various components were not functioning optimally. Most scientists who process instrumentation and controls the need for a mimature mass spectrome used the Quad 200 had no previous expegroup in Palo Alto, CA, for ElectronicAssociates, Inc. (EN,an analog computer rience in MS. A version of this RGA, the Quad 250, is pictured on p. 971 A. company headquartered in Long Branch, From 1964 to 1966 we built and delivstsument would have to withstand 900 “C NJ. The first thing we did after joining EAI ered more than 500 quadrupole RGAs, “bakeout” temperatures to be usable in was to accept our own proposal to carry many of which were used in the US. space out an evaluation of the QMS. Shortly afthis system. ter starting this evaluation program, Shoul- program. In 1966 we introduced a lowShoulders read Paul’s patents and decost, solid-state version of the QMS called ders’s group asked us to build several cided to proceed with the development of the QMS (Figure 1).His group built a p QMS instruments for them, because SRI’s the Quad 150, which further solidified the RGA market for the quadrupole. proximately 12 QMS prototypes during new president, Karl Fokkers, had deDuring 1966, Syntex Corporation tried 1959-62 and was able to achieve good cided that SRI should not be in the manuto acquire the quadrupole operation facturing business. With their help we performance (mass range to 500 Da with (called the ScientificInstruments Divitorr minimum detectable partial pres- built two QMS instruments in late 1963. sion) of EAI to use as a base for their new sure) by 1962. This work is reported in They allowed several of their best electronic engineers to “moonlight”with us to analytical instrument business. During several books and reports (1-4). the negotiations, I spent time with Carl show us the “tricks.” In 1962, P. M. (Mike) Uthe and I left From these prototypes we built the first Djerassi and Alejandro M a r o n i at Syntex Lawrence Livermore National Laboratory Research in Palo Alto. Through them and and I joined SRI to start a process concommercial QMS instrument, which we trols research group. My background was called the Quad 200 RGA (residual gas an- Djerassi’s MS group at Stanford (particularly Alan Duffield), I became aware of in electrical engineering, and Uthe was a alyzer). SRI had accumulated almost 100 physicist. We worked in the laboratory requests for quadrupole RGAs from vari- the potential of the GC/MS market. Hewlett Packard (HP) also became next to Shoulders’s group and became ous research laboratories by this time. aware of his research and the rather unThey gave us this “basket”of potential cus- quite interested in the QMS and in our o p eration as a possible complement to their F&M (chromatograph) Division, again increasing our awareness of the GC/MS market potential. HP bought a QMS from us in 1966,which ultimately wound up at their laboratory where it underwent detailed evaluation by Don Hammond and his physics group. Subsequently, after nine months of negotiation, the acquisition of our group by Syntex fell through. EN, throughout this period, expressed no interest in the GC/MS market, so I decided at the end of 1966 to find some other way to explore this new opportunity. Figure 1. Stanford Research Institute quadrupole.
University of California Radiation Laboratory report (UCRL 2209) published in 1953 and data in his personal notebooks. The first practical applications of the QMS appear to have been made at the Stanford Research Institute (SRI) in 1958. At that time, Ken Shoulders, a research physicist, initiated an advanced microelectronics research program. Its objective was to manufacture complex electronics systems built around miniature triodes. These triodes would be built inside a microfactory, which offered an ultraclean, ultrahigh vacuum (UHV; lo-” torr) environment. The triodes (lO1’/cu. in.) were
usual performance of the QMS. We thought the QMS could make an excellent sensor for measurement and control in chemical processes, and we sub sequently proposed research programs to Shell Development, Monsanto Research, and the Perkin-Elmer Corporation to evaluate and develop the instrument for such purposes. The initial cost of this evaluation program was estimated to be
970 A Analytical Chemistry, Vol. 66, No. 19,October 1, 1994
During the Syntex negotiations I spent many hours working with their US.chief financial officer (CFO), Roger Sant. Roger had previously been CFO of Wilkins Instrument and Research, working for Keene Dimick, the founder, before that company was acquired by Varian and became Varian Aerograph. When the attempt by Syntex to acquire EA1 foundered, Roger asked me what I planned to do. I replied that I had hoped to start a new company to develop and manufacture a GC/MS instrument using the quadrupole. He said he would like to work with me in starting such a company, and offered his help in raising capital, among other things. Roger asked Jon Amy, a personal friend and professor of chemistry at Purdue University, to evaluate the business plan I had prepared for the new company. Jon had many helpful suggestions that were incorporated into our final business plan. We founded Finnigan Instruments Corporation in January 1967 with an initial investment of $99,000 and guaranteed loan commitments of $250,000. Roger and I put up $25,000 each (Roger also guaranteed $75,000 in loans to the company), and T. 2. Chu, then general manager of Varian Aerograph, also invested $25,000. T. 2. would later become president and CEO of Finnigan and my partner in the business for the next 21 years. Two other important founders were Bill Fies, who came from SRI, where he had designed and built the quadrupole electronics, and Mike Story, who had worked with me at EAI and was responsible for quadrupole structure and vacuum chemistry develop ments. All of the founders were to remain at Finnigan Corporation in various roles until the company was acquired by Thermo Instrument Systems, Inc., in 1990. By 1967, GC had become a powerful and well-accepted method for separating compounds in mixtures. However, it had a serious drawback The compounds could not be easily or definitively identified, particularly in complex mixtures and matrices. Using a mass spectrometer to identify the compounds separated by GC seemed to be a perfect solution to this important problem. A quadrupolewas ideally suited for this task because it could take a full mass spectral scan much faster than the time required for a GC peak to pass.
Our major objective for the new company was to develop, manufacture, and market a GC/MS system using the SRIdeveloped QMS. We believed that its inherent advantages of simplicity,low cost, compactness, capability of operating at relatively high ion source pressures and, most important, ease of computerization would make it a logical choice for the GC/MS application. At that time the only commercially available GC/MS instrument was the LKB 90o0, which had just been introduced into the US.market. Design and construction of our first GC/MS system, the Model 1015 (shown in the photo on p. 972 A), was completed in one year. In January 1968 we delivered the first (prototype) system to the Stan-
nolds were responsible for operating the system. The Model 1015 had a mass range from 1to 750 Da with unit resolution over this mass range, scan speeds as fast as 50 ms for the mass and sensitivity of 1pg for methyl stearate and cholesterol as standards). The instrument used a singlestage glass jet separator to interface the gas chromatograph to the mass spectrometer, the design of which was given to us by Einer Stenhagen of the University of Goteborg, Sweden. It took us almost two years to perfect this interface so that we could achieve the desired performance with real-world samples. We also delivered two other prototype systems for testing and evaluation in early 1968. One went to Amy at Purdue University and the other to Djerassi at Stanford University. Many improvementswere made in the Model 1015 GC/MS instrument based on the evaluations of these prototypes. From the beginning of our GC/MS development program I was convinced that our ultimate success was dependent upon successful computerization of the quadrupole GC/MS system, so that the enormous amounts of data being generated, even in a short GC/MS analysis, could be handled. In part, my conviction was based on my observations of the successful computerization of the first Model 1015 by the Stanford Medical School group. This computerization enabled them to solve dif6cult peptide sequencing prob
I The EA1 Quad 250 Residual Gas Analyzer.
lems. They devised both a dedicated computer approach, using a LINC-8 computer (predecessor to the PDP-8), and time sharing, with the so-called ACME system, which included IBM models 360 and 1800 linked together. It became obvious to us early on that the dedicated data system approach was more suitable, both in terms of uptime and cost, for a commercial GC/MS system. During 1968we accepted an order from Evan Horning of Baylor Medical College for a computerized GC/MS system (GC/ MS/DS) to be delivered within one year. We were not really sure how we were going to carry out our commitments to Baylor, but shortly after accepting the order, E.V.W. Zschau, a professor in the Stanford Business School, approached me for product ideas for a new company he was just forming. I suggested that they develop a data system for our GC/MS instru-
Analytical Chemistry, Vol. 66, No. 19, October 1, 1994 971 A
The Model 1015, the first GC/MS system built at Finnigan Corp.
ment, which we would market exclusively for them. Zschau and his associates formed a company-System Industries, 1nc.-to develop this system inside our facility in mid-1968. Their product, the System 150, was the first success of this computer peripherals company, which located in Milpitas, CA Zschau later became a US.congressman for Silicon Valley. The first commercial GC/MS/DS instrument, the Model 1015/System 150 shown in the photo on p. 973 A, was introduced at the fall ACS show in New York City in 1969and subsequently delivered to Homing’s Group at Baylor Medical College. About that time, HP introduced their quadrupole (dodecapole) GC/MS system based on the technical efforts of Bob Board and his colleagues. Initially, we were worried about having such a formidable competitor as HP. As it turned out, they not only validated the QMS techniques, but ensured that all successful competitors must achieve the high standards of quality and performance that c u s tomers had learned to expect of HP. This benefited the customers and the competitors and helped to broaden the market. 972 A Anal’ical
With the introduction of the Model 1015/System 150, we believed that GC/MS was now poised to take off. However, in the 18 months following its introduction, we sold only one system-a very big disappointment. Most potential users of GC/MS/DS (or their bosses) wanted us to hook it up to their already existing time-shared computer systems (most often an IBM 360). It was not economically feasible for us to consider this approach. Furthermore, we were convinced that the dedicated data system approach was more suitable for GC/MS, so we put our efforts into convincing the potential customers to go that route. This was the lowest period in the history of Finnigan Corp. (1969-70). The U.S. economy was depressed; we were not receiving orders and we were rapidly running out of money. In 1970 we initiated a large cutback in staff to reduce expenses, and we looked in vain for corporate partners. Environmental market development
The formation of the Environmental Protection Agency (EPA) in late 1970 pro-
Chemistry, Vol. 66, No. 19, October 1, 1994
vided the big break for computerized GC/MS and for Finnigan Corporation. Analytical environmentaltesting could have serious consequences. Plants could be shut down, or large lines imposed, if pollutants were discharged beyond permitted quantities. GC/MS was highly desirable for these applications because the combination of GC retention time and MS spectrum gave unambiguous proof of the presence of pollutants. Any technique that left ambiguity in the analytical results was likely to lead to continual controversy and litigation. We started working with several EPA environmental research laboratories during 1970 before the actual formation of EPA, carrying out complex analyses of pollutants in wastewater. Based on early successful results, EPA decided in mid1971to purchase 20 computerized GC/MS systems for its various research and monitoring laboratories throughout the country. Following an evaluation of all major GC/MS manufacturers, Finnigan was chosen to supply its Model 1015/System 150 for all 20 laboratories. These EPA laboratories carried out extensive analyses over the next several years. Three EPA scientisesteve Heller, John McGuire, and Bill Budde-wrote the following evaluation of computerized GC/MS in a feature article in Enuironmental Science & Technology in 1975 (5):“The identification of pollutants at the part-perbillion level with a high degree of confidence in the result has become nearly routine in several EPA laboratories. What was once an impossible task for a staffof 100 working six months sometimes can be accomplished by a skilled individual in a few hours.” With this kind of endorsement, one would thiithat computerized GC/MS would soon become a primary analytical technique for organics analysis. Such was not the case. Only the major petrochemical manufacturers felt they could afford the $150,000+ price tag required to buy a computerized GC/MS system in the early 1970s. (That would translate into a price of $450,000 today.) The remainder of the regulated community resisted the push toward GC/MS and continued to use GConly methods. What was more worrisome to us was that the EPA officials responsible for man-
dating the methods to be used by industry also believed that the cost and complexity of computerized GC/MS was too high to justify it as a required method. At EPA’s Environmental Monitoring and Support Laboratory in Cincinnati, the official who was responsible for proposing methods for pollution measurement told me in 1978 that “the day he proposed GC/MS as a mandated method would be his last day at the EPA” He believed that he would be fired for making such a poor decision. At this point, we at Finnigan realized that we would have to demonstrate the cost-effectivenessand reliability of computerized GC/MS to both the regulators and the regulated community. In addition, we would have to show that there were qualiied service laboratories available to perform GC/MS analyses at a reasonable cost for those who could not afford to set up their own laboratory. To do this, we initiated a survey in mid1978 to measure the cost-effectivenessof GC/MS versus other accepted techniques-specifically GC-as realized by competent laboratories using both techniques. We included in the survey approximately 100 chemists working in 60 government, industrial, and private contract service laboratories. We completed the survey in the fall of 1978. During the survey we met and discussed the issues with many of the leading people in both the regulatory and the regulated communities as well as with trade associations of the regulated community. We realized that if computerized GC/MS
I A Irist r u ment
Labor related
Instrument
Labor related
I
I
I
Figure 2. Comparison of costs for priority pollutant organic analysis by QC and GCIMS. (Adapted from Reference 6.)
were to become a mandated method, it would require the agreement or at least no veto from the regulated community, as represented by its trade associations. In general, we found that the regulated community (industrial companies) preferred a definitive method such as GC/MS, which produced data that were legally defensi-
P
I
The Model 101S/System 150, the first computerized GC/MS system.
ble. In the survey, we found that there were at least six different organizations withii the-EPAthat also had to agree to its use as a mandated method. A veto fi-om any one of them could squash our hopes for GC/MS as a mandated method. During 1978, I enlisted the assistance of a former EPA assistant administrator, Roger Strelow (then in private law practice), to help us “learn the ropes’’ at EPA We were able to present our survey results to each of the half dozen or so parts of EPA involved in the decision process and, in most cases,to get their active cooperation. We also determined from our survey that there were some 52 contract service laboratories in the United States capable of carrying out “priority pollutant” analyses for industrial companies at a reasonable cost. EPA subsequently carried out a parallel evaluation of GC/MS costs, reliability, and the availability of contract service laboratories before proposing GC/MS as a mandated method. The results of this survey were p u b lished in May 1979 in an article entitled “Priority Pollutants 11-Cost Effective
Analyfical Chemistry, Vol. 66, No. 19, October 1, 1994 973 A
Table 1. Data quality of priority pollutant organic analysis by GC and GCMS
Baselneutrals
Analysis,” in Enuironmental Science & Technology (6). Table 1and Figure 2,excerpted and adppted from this article, summarize these results, which show that the cost of performing an analysis by GC/MS is slightly less than by GC only, on a cost-per-analysisbasis, whereas the reliability of the GC/MS analysis is considerably better for most compounds. To our knowledge, this was the first published comparison of environmentalanalytical methods that considered cost per analysis. Earlier comparisons considered only the total cost of each instrument. In 1979, computerized GC/MS was formally proposed as a part of the Clean Water Act Series 600 methods (along with GC), popularly known as the 304(h) methods, for analysis of organic pollutants in water. In 1982, GC/MS was included in Solid Waste Manual SW-846,which mandates methods for measurement of organic pollutants in hazardous waste materials and in groundwater in the Resource Conservation and Recovery Act and Superfund programs. Although the final approval of the Series 600 methods did not come until 1984 (7), the regulated community adopted them broadly in 1979. The environmentalbusiness had a dramatic effect on the use of computerized GC/MS, as well as on suppliers such as Finnigan. Our business, which was about $2 million/year in 1971 when we received
used by technicians with little specialized training. But as I look to the future, there is one application field that could have a similar impact on the MS market as was made by environmental analysis in the past-bioscience. The explosion in bioscience and biotechnology research, as seen in the Human Genome Project and related programs, will require that MS be used for many applications, including the mapping and sequencing of genes and the characterization of proteins. Instruments for routine, low-cost, highperformance bioscience applications will be computerized benchtop systems using quadrupole and quadrupole ion trap MS/MS technology interfaced to LC,c a p illary electrophoresis, and other separation techniques. These systems will use electrospray and atmospheric pressure chemical ionization. Improvements in data system power and automation will allow biologists and biochemists to use the systems with ease, even for the most complex analyses. Finally, as regulations spurred the growth of MS for environmental analysis, MS techniques may be mandated by the Food and Drug Administration or other regulatory agencies for health safety reasons. If this happens, regulations again will have a major effect on the size and growth of the MS market.
the first EPA order, rose to more than $130 million by 1988, with the environmental segment accounting for more than half of this total. Environmental applications require high throughput of very complex samples, which would not be possible without the use of a computer. Within a few years of EPAs first order for 20 computerized GC/MS systems, most of the instruments ordered from us included a dedicated data system. In addition, many industries that first used computerized GC/MS for Conclusion environmentalanalysis quickly adopted it for other applications. By 1984 Finnigan About two years ago, I had the good fortune to meet and talk at length with Wolfoffered no GC/MS systems without a gang Paul when he gave the plenary lecdata system. ture at the American Society for Mass The growth of GC/MS and the trend Spectrometry annual meeting in Nashtoward computerized systems was also predicted by other manufacturers, such as ville, TN. I expressed my admiration for his work, which led to the Nobel Prize, esHP. Their mass selective detector bem e a successful product in the environ- pecially his invention of the quadrupole and ion trap mass spectrometers. Paul mental market as well as in other marminimized his role and stated that he ket segments, and helped drive the inthought the job we had done in develop creasing demand for low-priced GCIMS ing and commercializing the quadrupole systems designed for a broad range of and ion trap mass spectrometer was the routine applications. more d ~ c u land t impressive part in making them successful products, and he Looking to the future wrote that message to me on a copy of his At this point, it is appropriate to take a Nobel address. brief look into the future. I have already I believe that it takes each of the ingre mentioned the trend toward the integradients mentioned above to generate a suction of MS with other techniques such as chromatography, and the simplification of cessful new product or technology, and many of us play a role. I feel lucky to have the technique so that it can be readily
974 A Analytical Chemisrry, Vol. 66, No. 19, October 1, 1994
played a role in the development and commercialization of the quadrupole mass spectrometer but realize that there were many others whose contributions were equally or more important: people such as Bill Fies and Mike Story. Bill was the guiding genius in developing the quadrupole electronics, both at SRI and Finnigan Corporation.Mike was responsible for many of the critical improvements in the quadrupole filter design and led the engineering development of the first quadrupole GC/MS system. To these men, who often get little credit for their contributions, I and the MS community are deeply indebted. References (1) Shoulders, K. R “Research in Microminiaturization Using Electronic Machining Techniques”; SRI Report, Division of Engineering Research, 1958. (2) Shoulders, K. R In Advances in Computers; Alt, F., Ed.; Academic Press: New York, 1961; Vol. 2. (3) Shoulders, K. R In Microelectronics and Large Systems; Spartan Books, Inc., John Wiley & Sons: New York, 1965. (4) Kelly, J. “Research in Microminiaturization Using Electron-ActivatedMachine Techniques”; SRI Report, Division of Information Science and Engineering, 1967. (5) Heller, S. R; McGuire, J. M.; Budde, W. L. Enuiron. Sci. Technol. 1975, 9,210-13. (6) Finnigan, R E.; Hoyt, D. W.; Smith D. E. Enuiron. Sci. Technol. 1979,13,534-41. (7) Fed. Regist. 1984,40, 136.
Reagent Chem,ia Eighth Edition eagent Chemicals is the only resource of its kind that provides specifications
and analytical procedures t o assure the quality of your chemicals. ACS specified reagent chemicals are the choice of most organizations such as APHA, ASTM, FCC, SEMI, USP, etc., and many regulatory agencies, such as the EPA. Improved and expanded, the eighth edition of this authoritative reference now comes in a user-friendly format that makes look-up quick and easy. In it you’ll find all the necessary information on 0 0 0 0 0 0 0 0 0 0 0
0
Robert E. Finnigan (125 Los Altos Ave., Los Altos, CA 94022) is a consultant to Thermo Instrument Systems, Inc., and Finnigan Corporation, and is a member of the boards of directors of three entrepreneurial analytical instrument companies. He also is an adviser to Hambrecht & Quist’s Environmental Technology Fund, a venture capital fund that invests in small environmental companies. He received a B.S. degreefrom the US.Naval Academy and an M.S. degree and Ph.D. from the University of Illinois. He and his wife Bette live in Los Altos and Arnold (Central Sierra), CA. They have seven children and seven grandchildren.
R
! !
atomic absorption spectrophotometry chromatography colorimetry and turbidimetry direct electrometric methods gravimetric methods measurement of physical properties reagent solutions solid reagent mixtures solvents for special purposes specifications and tests standard volumetric solutions titrimetry
New in this edition are a section on determining detection limits, the general elimination of boiling point and density specifications, the use of LC in assay determinations, and a section on preparation of volumetric solutions. Twenty-four new reagents have been added. Updated methods include gas chromatography where capillary columns are now used, water determinations where coulometric methods have been added, and the replacement of flame emission techniques by atomic absorption for metal determinations. In addition, the general methods for chromatography and atomic absorption have been extensively revised t o reflect their practical use in today’s typical analytical laboratory. 815 pages (1993)Clothbound ISBN 0-8412-2502-8 $149.95 American Chemical Society Distribution Office Dept. 51 1155 Sixteenth Street, NW Washington, DC 20036 Or CALL TOLL FREE (In Washington, DC. 872-4363) and use your credit card!
Analytical Chemistry, Vol. 66, No. 19, October 1, 7994 975 A
