A Brief History of Bio Products Laboratory and the Elstree Site By Tim Sandle

What is BPL? BPL is a not-for-profit organisation of the NHS and produces a range of plasma derived therapeutic products. The plasma is fractionated by a process which separates out the plasma components into different product groupings. These products include coagulation factors for the control of haemophilia (A and B) and other inherited bleeding disorders; specific and nonspecific immunoglobulins (antibodies) for the treatment of people born with weak immune systems; and albumin for those who need a restoration of their circulating blood volume. These products are distributed around hospitals in England and Wales, with any excess sold on a global market with all proceeds returned to the NHS.

The plasma is separated and purified by a process called Plasma Fractionation. Plasma arrives at BPL frozen. After quarantine, the plasma is sent for processing. The first product (cryoprecipitate) is separated and is used to process the clotting factors. This is performed by separating plasma from individual packs; crushing and thawing under controlled conditions, and extracting the clotting factors from the thawed material. Following purification and concentration, the finished bulk solutions are sterile filtered and aseptically filled. After the clotting factors have been separated, the remaining liquid is bulked in large capacity vessels and centrifuges in sub-zero conditions. Proteins are separated by the addition of

ethanol and other reagents. The precipitates are further processed to remove residual alcohol and processed as albumins or immunoglobulins. These products are also are sterile filtered and aseptically filled. During processing a number of quality checks are performed by BPLs Quality Assurance and Quality Control departments. Lister Institute of Preventative Medicine1 In 1902 Dagger Farm in Aldenham, Hertfordshire was sold to the Lister Institute of Preventative Medicine. The farm was located along the appropriately called Dagger Lane, were a nineteenth century murder by stabbing had occurred. The Lister Institute was established by Joseph Lister in 1891 (by then Baron Lister of Lyme

Regis) to undertake scientific research into the

causes, prevention and treatment of disease and to prepare and supply protective and curative materials such as vaccines and antitoxins. The reason the Lister Institute purchased the farm was because of protests from the now archaic AntiVaccination League, and the need for body, founded by Joseph Lister in 1891, to have access to farm animals in order to develop life saving vaccines to treat then serious illnesses like diphtheria and scarlet fever. Arguably the most famous scientists to work at Elstree was Joseph Lister (1827 1912).

Lister is credited with the discovery of how wounds became infected during surgery and developed the first anti-septic products (starting with carbolic acid in 1869, which when first used by surgeons reduced mortality during surgery substantially).

The 35 acre Elstree site was used to house various farm animals, which were used to develop life saving vaccines to treat then serious illnesses like diphtheria and scarlet fever. Queensbury Lodge, built in 1886 and currently BPLs administration centre, was the location of the research laboratories.
1

Source material: http://www.lister-institute.org.uk/scientific.htm

A number of eminent scientists worked at the Lister Institute including Harden (the discoverer of co-enzymes) and the microbiologist MacConkey. Under Listers direction many scientists from around the world worked in the Institute undertaking research targeted at preventing disease. These included Petri and MacConkey, neither who are instantly recognisable, but whose work was of great importance. Richard Julius Petri (1852 1921) was a German bacteriologist. His greatest contribution was developing the petri dish for the culture of micro-organisms which is now staple in laboratory work. Petri dishes are filled with agar (a substance derived from seaweed), which is jelly like and allows bacteria to grow, It was through a culture on a Petri dish that Alexander Fleming later discovered penicillin. Alfred MacConkey (1861 1931) was in charge of the Lister Institute during the 1920s. Working from Queensbury Lodge, one of his contributions was to develop a bacteriological medium for the detection of the pathogen E. coli, which is still used in many laboratories today. MacConkey, by all accounts, was a difficult man to work for and went under the nickname of the dictator. Other eminent persons to work at the site included Douglas McClean, Harriett Chick and the unfortunate Thomas Carlyle. McLean played a key role in the 1930s in helping to produce the first mass produced vaccines against diphtheria and tetanus for the UK population. The life-time of these vaccines were extended by the pioneering process of freeze-drying (a technique whereby water is removed which extends the stability). Freeze-drying later became pivotal in the development of therapeutic blood products manufactured from the Blood Products Laboratory. Harriett Chick played a leading role in producing the first disinfectants to be targeted against specific germs. These were developed after the unfortunate incident involving Thomas Carlyle in 1903. During this year the first cases of a new pneumonic plague reached Scotland from India (the plague being carried first on rats, then to fleas and

finally to people). The scientists at the Lister Institute played an important role in developing an anti-serum. This was not without cost as Carlyle contracted the plague and died within three days in the Lister Cottages along Dagger Lane (reputedly cottage number 1, which is said to be haunted). This remains the last known death from plague in Hertfordshire.
In 1954, the Lister Institute shared the Elstree site with the newly formed Blood Products Laboratory. In 1978, due to financial pressures and a decline in the demand for smallpox vaccines, the Lister Institute was forced to leave due to financial problems and BPL took sole control of the site. BPL During the 1940s, Brinkhous and McFarlane discovered that transfusions using whole blood or plasma provided a means of FVIII replacement. Applications using this early discover were limited due to naturally low concentrations of this anti-haemophilic factor in blood and plasma and volume constraints in the circulatory system. During this time, Professor R. A. Kekwick, working at the Lister Institute undertook experimental and production work with A.S. McFarlane. The two scientists devised a process to clarify outdated blood plasma to render it suitable for transfusion2. In 1943, Kekwick was appointed Head of the Lister's Biophysics Division, Kekiwick established the Blood Filtration Unit and he and his team worked on methods of freeze-drying plasma and then of separating out proteins in blood plasma. These early products were used to meet the needs of the Armed Services and civilian establishments. In 1948 the Blood Filtration Unit came under the joint management of the Medical Research Council (MRC) and the Lister Institute, and the name was changed to the Blood Products Research Unit and it occupied the newly built laboratories (or Building 25). The aim of the Unit was directed towards the preparation of plasma fractions for clinical use3.

2 3

Source material: http://www.bath.ac.uk/ncuacs/guidei-k.htm#KekwickRA Source material: BPL Staff Handbook, 1992

In 1954, the Government wished to establish a site for increased production of blood products. This followed on from the importance of blood in therapeutic medicine, the need for blood products during the Second World War (particularly the use of albumin 4) and the formation on 26th September 1946 of the National Blood Transfusion Service. It had also been discovered that a second form of haemophilia (Haemophilia B) existed, which was treatable with blood protein called Factor IX. An agreement was reached between the Government, MRC and the Lister Institute and the Blood Products Laboratory was established with funding from the Ministry of Health. Enlarged facilities for plasma fractionation and freeze-drying were established. The Early Years Work in the development of blood products continued. In the 1950s, Kekwick developed a method of fractionating out a fibrinogen fraction rich in Factor VIII, the antihaemophilic globulin. This led to the first clinical use of Factor VIII in treating haemophilia in 1957 and the need for large scale plasma fractionation, which BPL provided5. In 1959, a group led by Pool discovered that cryoprecipitate - the cold, insoluble globulin precipitate formed during the slow thawing of plasma contained a five-fold higher concentration of FVIII compared to that of plasma. By 1964, it was shown that cryoprecipitate could be separated by centrifugation and stored frozen. Because cryoprecipitate contained other proteins, such as fibrinogen, albumin and immunoglobulins, these needed to be extracted through the process of fractionation using ethanol. The use of fractionation had been developed by the American Doctor Edwin Cohn in the 1940s.

Source: Blood - An Epic History of Medicine and Commerce; Douglas Starr; London: Little, Brown, 1999; ISBN 0316911461 5 Source: http://www.bloodbook.com/trans-history.html

Fractionation amount of

also Factor

allowed VIII to

the be

concentrated to over 400 times the natural concentration found in blood plasma. By the late 1960s the process of freeze-drying (lyophilisation) was used to produce, concentrate and preserve Factor VIII products. Activity increased at BPL throughout the 1960s and 1970s with the introduction of cryoprecipitate (in 1964) and more purified forms (in the 1970s) for the treatment of haemophilia. Some of the other proteins extracted through fractionation could be developed into different blood products. The first major non-coagulation factor to be developed was the Anti-D immunoglobulin for treating rhesus-negative mothers. In 1978, the Lister Institute sold the entire Elstree site to the Government. The distinction of the scientists and technicians dining in separate canteens was thus ended as BPL took sole occupancy of the site. The average wage for a laboratory technician at BPL was 25.67 per week6. The running of BPL was transferred to the North West Thames Regional Health Authority as an interim measure. In 1982 a Special Health Authority was created called the Central Blood Laboratories Authority (CBLA). The CBLA administered BPL, PFL, Biomedical Services and the Bristol based International Blood Group Reference Laboratory (IBGRL) for approximately ten years. PFL In 1967 the Plasma Fractionation Laboratory (PFL) opened in Oxford (at the Churchill Hospital, Headington). PFL, staffed by a small number of people, was established as BPLs pilot plant and to produce special products for the treatment of rare forms of haemophilia.

Source: Alice Kidd in The Crest, Summer 1990

The Oxford laboratories were a highly innovative research centre, until their closure in 1992 when all operations and staff were transferred to BPL. PFL developed the first heat treatment process for Factors VIII and IX in the mid-1980s. BPLD The Blood Products Laboratory Diagnostics (BPLD) operation was set up in 1986. The aim of the operations department was to provide a service for blood grouping tests, for the identification of correct blood groups of donors and patients, and diagnostic kits, such as screening cells, for various blood centres and hospitals. BPLD was closed in 1995 and its operations were transferred to different centres within the blood transfusion service.

1980s: Expansion of demand In 1982, a massive increase in capital expenditure took place, at around 60 million, to allow for a large, modern manufacturing unit capable of greater production of blood products. The size of the BPL site increased when Sir William Maycock sold his house and grounds (which included an orchard). The factory had to be designed so that it fitted into the local green belt of leafy Hertfordshire7. The new development was initiated when the then Minister of Health, Norman Fowler, laid the foundation stone for what was to become the state-of-the-art factory. The new, state-ofthe-art factory was opened by HRH the Duchess of Gloucester on 29th April 1987, which frames the recognisable wedge-like image for passers by.

The mid-1980s also saw a growth in staff number from about 200 to around 400 employees representing a variety of administrative, financial and scientific disciplines. Many staff were drawn from the nearby towns of Borehamwood and Watford. Staff number increased to 500

Source: Blood Products Laboratory: Long Term Management Plan, April 1987, Building Design Partnership

by the late 1990s. Industrial relations developed into one of partnership between BPLs Executive and the trade union MSF (later Amicus). A greater focus on Quality Assurance took place and a range of specialist functions were introduced, such as, a dedicated microbiology department to test the quality of the manufacturing environment. Key changes to manufacturing were introduced with a greater emphasis on patient safety; improved aseptic filling operations and sterile filtration of the product.

1990s: Commercial development In 1990, following the establishment of the internal market in the NHS, Blood Products Laboratory changed its name to Bio Products Laboratory, although the BPL acronym was retained. At the same time the Government introduced a charging mechanism for BPL products to NHS customers. All main BPL products became licensed and BPL subject to medical inspectorate visits. In 1991, BPL received a special mention in the House of Commons for its role in the Gulf War through providing special immunoglobulin products as part of Operation Granby in association with the Chemical Defence Establishment at Porton Down. In 1993, the CBLA was dissolved and BPL became part of the newly formed special Health Authority: the National Blood Authority (NBA). This brought BPL and IBGRL together with the blood transfusion centres and donor collection service, previously under Regional Health Authority control, to form the National Blood Services. This change was to allow for greater re-sourcing and national strategy.

The 1990s saw improved techniques for viral removal and inactivation. A specially designed area of the factory the Viral Secure Area (VSA) was established and solvent detergents steps added to destroy a spectrum of blood borne viruses. Further investments into buildings took place and dedicated buildings for Engineering, laboratories and R&D were built in the early 1990s. In 1998 the theoretical risk of transmission of nvCJD resulted in a major change for BPLs operations. The factory underwent a major sanitisation exercise and plasma was purchased from blood centres in the USA. The future The future for BPL will be both consistent and constantly changing. BPL will continue primarily as a plasma fractionator to supply IgG to the patient population. This will continue to be BPLs biggest growth area as there is a shift away from manufacturing Factor VIII and albumin at previous levels. The twenty-first century will see BPL operating in Europe and in the USA, which will keep BPL evolving and adapting in response to change. The future holds much to look forward to and much to achieve.

BPL History Timeline

Year 1851 1891 1902 1943 1946 1953 1954 1964 1967 1968 1978 1985 1986 1987 1990

Event Earliest mention of Dagger Farm at the BPL site in the Public Records Lister Institute is formed in London by Joseph Lister Dagger Farm is sold to the Lister Institute of Preventative Medicine. The Blood Filtration Unit is set-up at the Lister Institute. National Blood Transfusion Service is formed MRC funds building of blood laboratories at the Elstree site Blood Products Laboratory (BPL) becomes operational. Cryoprecipitate introduced. Plasma Fractionation Laboratory (PFL) opens. Anti-D introduced Lister Institute closes. BPL is the sole occupier of the Elstree site. Heat treated Factor VIII (8Y) and Factor IX developed. Blood Products Diagnostics opens. New factory (Building 27) opens Technical department (Building 21) opens.

1990

Change of name from Blood Products Laboratory to Bio Products Laboratory Surrendered Crown Immunity. NHS Internal Market came into place PFL closes.

1991 1991 1992

1993 1993 1994 1995 1996 1998 1998 2000 2004

R&D building opens National Blood Authority is created to oversee BPL and the blood transfusion service. Replenate and Replenine launched. Blood Products Laboratory Diagnostics closes. Vigam-S launched. BPL moves from UK plasma to plasma from the USA due to concerns about nvCJD. Vigam Liquid launched. Replenine-VF launched. Solvent detergent process for IgG developed. Optivate launched Subgam launched. FDA approval gained

2009

References and Further Reading Blair, J. S. G. (1998): Centenary History of the Royal Army Medical Corps 1898 1998, Scottish Academic Press, Edinburgh Blundell, J. (1818): Some Account of Obstinate Vomiting, in which an Attempt was made to Prolong Life by the Injection of Blood into the Veins, Medical Chirurgical Society, Vol. 10, pp296-311 Giangrande, P. L. F. (2000): History of Blood Transfusion, British Journal of Hematology, 110, pp758-767 Keynes, G. (1967): Tercentenary of Blood Transfusion, British Medical Journal, 4, pp410-411 McCullough, J. (2003a): Transfusion Medicine in Hardin. R.I., Lux, S.E. and Stossel, T.P. Blood: Principles and Practice of Haematology, 2nd Edition, LippincottWilliams and Wilkins, Philadelphia, pp2011-2068 Meulenbroek, A. J. (2002): 'From blood to medicinel', Sanquin, Amsterdam. Reproduced at: http://www.sanquin.nl/sanquineng/sqn_From_blood_to_medicine.nsf?OpenDatabase Rivett, G. (1998): From Cradle to Grave: Fifty years of the NHS, Kings Fund, London

Starr, D. (1998): Blood: An epic history of medicine and commerce, Knopf, New York