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 non-

specific 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 BPL’s 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 Anti-

Vaccination 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 BPL’s 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 Lister’s

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 Source material: http://www.bath.ac.uk/ncuacs/guidei-k.htm#KekwickRA3 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 anti-

haemophilic 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.

4 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 also allowed the

amount of Factor VIII to 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 BPL’s

pilot plant and to produce special products for the treatment of rare forms of haemophilia.

6 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-of-

the-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

7 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 BPL’s

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 BPL’s

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 BPL’s 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 Event

1851 Earliest mention of ‘Dagger Farm’ at the BPL site in the Public Records

1891 Lister Institute is formed in London by Joseph Lister

1902 Dagger Farm is sold to the Lister Institute of Preventative Medicine.

1943 The Blood Filtration Unit is set-up at the Lister Institute.

1946 National Blood Transfusion Service is formed

1953 MRC funds building of blood laboratories at the Elstree site

1954 Blood Products Laboratory (BPL) becomes operational.

1964 Cryoprecipitate introduced.

1967 Plasma Fractionation Laboratory (PFL) opens.

1968 Anti-D introduced

1978 Lister Institute closes. BPL is the sole occupier of the Elstree site.

1985 Heat treated Factor VIII (8Y) and Factor IX developed.

1986 Blood Products Diagnostics opens.1987 New factory (Building 27) opens

1990 Technical department (Building 21) opens.

1990 Change of name from Blood Products Laboratory to Bio Products Laboratory

1991 Surrendered Crown Immunity.

1991 NHS Internal Market came into place

1992 PFL closes.

1993 R&D building opens

1993 National Blood Authority is created to oversee BPL and the blood transfusion service.

1994 Replenate and Replenine launched.

1995 Blood Products Laboratory Diagnostics closes.

1996 Vigam-S launched.

1998 BPL moves from UK plasma to plasma from the USA due to concerns about nvCJD.

1998 Vigam Liquid launched. Replenine-VF launched.

2000 Solvent detergent process for IgG developed.

2004 Optivate launchedSubgam launched.

2009 FDA approval gained

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, Lippincott-Williams and Wilkins, Philadelphia, pp2011-2068

Meulenbroek, A. J. (2002): 'From blood to medicinel', Sanquin, Amsterdam. Reproduced at: http://www.sanquin.nl/sanquin-eng/sqn_From_blood_to_medicine.nsf?OpenDatabase

Rivett, G. (1998): ‘From Cradle to Grave: Fifty years of the NHS’, King’s Fund, London

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