Bio Products Laboratory: celebrating sixty years of excellence

By Tim Sandle

Introduction

In 2014 BPL reaches its sixty year, diamond jubilee.

This milestone marks decades of innovative plasma derived products; high volumes of
production; and global distribution of a high quality therapeutic product.

Over the past sixty years BPLs operations have seen many changes. To meet those
challenges, BPL has changed its infrastructure and its logistics and distribution; switched
plasma supply from the UK to the USA; research and developed new products and founded
new markets.

During the sixty years BPL has acted in a dynamic and competitive marketplace. The
organisation has also moved through different strategic models and ownerships. This period
has seen the demand for products increase as more and more patients are successfully treated
and are able to live normal lives.

Underlying these changes there has been an element of constancy. BPL has remained on the
same pleasant site in rural Hertfordshire. The raw material from which BPL manufacturers
its products is still fundamentally the same raw material, the process by which BPL breaks
that raw material into its component parts and extract it is still essentially the same process.

BPL has met these challenges through its highly trained and committed workforce. In sixty
years, the number of people working at Elstree has increased significantly. BPL successfully
engages a dynamic and competitive marketplace and continues to make products that not
only change the lives of the patients but also change the lives of families and friends whose
loved ones benefit from them.

Looking forward to the future sees further exciting challenges on the horizon with upgrades
to plant and infrastructure and the ability to be able to produce new ranges of products to take
to new and expanding markets.

This booklet looks over BPLs history the success and challenges and highlights what a
remarkable organisation BPL is and how its history is, in many ways, the key building block
for BPLs future.


Bio Products Laboratory

BPL is a pharmaceutical company, owned by BPL Holdings, which 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
with weak immune systems; and albumin for those who need a restoration of their circulating
blood volume. These products are produced under the requirements of Good Manufacturing
Practice and they are distributed globally.

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 also sterile
filtered and aseptically filled.

During processing a number of quality checks are performed by BPLs Quality Assurance
and Quality Control departments. The product is then distributed through a global supply
chain.

The history of BPL

The foundations: The Lister Institute

BPLs history lies with a small farm in the Parish of Aldenham in Hertfordshire and with one
of Britains most eminent scientists, Joseph Lister.

The farm in question was Dagger Farm, a smallholding which dates to circa 1850. In 1902
Dagger Farm was sold to the Lister Institute of Preventative Medicine. The farm was located
along the appropriately called Dagger Lane (the site, it is alleged, where a man was stabbed
to death in the mid-nineteenth century).

The Lister Institute was established by Joseph Lister in 1891 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. Joseph Lister (the 1st Baron Lister) was a
British surgeon and a pioneer of antiseptic surgery.

If we had nothing but pecuniary rewards and worldly honours to look to, our
profession would not be one to be desired. But in its practice you will find it to be
attended with peculiar privileges, second to none in intense interest and pure
pleasures. It is our proud ofce to tend the fleshly tabernacle of the immortal
spirit, and our path, rightly followed, will be guided by unfettered truth and love
unfeigned. In the pursuit of this noble and holy calling I wish you all God-speed.
(Joseph Lister quoted in In John Vaughan, 'Lord Lister', The Living Age (1918),
297, 361).


The Lister Institute was the first medical research charity in the U.K. and it was originally
based in Chelsea, London. The need to find a location to conduct vaccine research and
development was the main reason for Listers purchase of Dagger Farm. The 35 acre Elstree
site was used to house various farm animals, which were used to develop lifesaving 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.
Such research included the study of plague and its transmission. The study of plague resulted,
in the 1930s, of one of the last reported plague deaths in England when an unfortunate
laboratory technician contracted the pathogenic bacterium and later died in 1 Lister Cottages.

During the height of the Lister Institutes success a number of eminent scientists worked at
Elstree, including Harden (the discoverer of co-enzymes) and the microbiologist MacConkey.

In 1954, the Lister Institute shared the Elstree site with the newly formed Blood Products
Laboratory (the reasons for which are unravelled below). In 1978, due to financial pressures
and a decline in the demand for smallpox vaccines, the Lister Institute was forced to leave
and BPL took sole control of the site. Today the Lister Institute exists as a science funding
body, where it awards the Lister Institute Research Prize Fellowships to researchers working
on infectious disease.

The development of blood products

Blood products fall into three main groupings: coagulation factors (to treat bleeding
disorders); immunoglobulins (antibodies essential for a functioning immune system) and
albumin solutions (which restores blood volume or aids the treatment of burns). While such
products are established therapeutic products they are only around seventy years old. The
origin of these blood products is bound up in the history of BPL.

The fractionation of plasma, where blood proteins can be extracted to make therapeutic
products, was developed by Edwin Cohn for the U.S. Army at Pearl Harbour in early 1940;
and later unprocessed plasma, supplied by the U.S. as part of a national Plasma for Britain
campaign, was used as a medical treatment by the British Army at Dunkirk. These starting
points led to considerable government interest and to the development of blood products in
the U.K.

During the 1940s, British scientists Brinkhous and McFarlane discovered that transfusions
using whole blood or plasma provided a means of FVIII replacement. Applications using this
early discovery were limited due to naturally low concentrations of this anti-haemophilic
factor in blood and plasma and volume constraints in the circulatory system. Nonetheless,
this discovery was the foundation of the U.K.s establishment of a blood products research
centre.

The U.K.s association with blood products began with R. A. Kekwick who established the
Blood Filtration Unit (BFU) in 1943 at the Lister Institute. Kekwick, employed at the Lister
Institute as head of the Biophysics Division, 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 transfusion. Kekwick began working 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 (BPRU) and the Unit occupied a set of newly built laboratories (now no longer
in existence, having been replaced by the current manufacturing facility). The remit of the
Unit was directed towards the preparation of plasma fractions for clinical use. The BPRU was
the direct forerunner to BPL.

The founding of BPL

While the research unit was important in the development of blood products, it was not
equipped to deal with the growing demand from the health service. This heightened medical
interest followed on from the appreciation of the importance of blood in therapeutic
medicine; the continuing interest in blood products following the Second World War
(particularly albumin, which had proved effective at treating injured soldiers); and the
formation on 26th September 1946 of the National Blood Transfusion Service, which
presented the possibility of a steady plasma supply. The desire for blood products was also
driven by further scientific discoveries; for example it had recently been discovered that a
second form of haemophilia (Haemophilia B) existed, which was treatable with a blood
protein called Factor IX.

An agreement was reached between the Government, MRC and the Lister Institute for a new
facility. With the agreement secured, the Ministry of Health constructed a manufacturing
facility and the Blood Products Laboratory was established in April 1954 for 175,000.
Because the research unit was established within the grounds of the Lister Institute, it seemed
a natural place for the BPL facility to be based. As part of the site development, enlarged
facilities for plasma fractionation and freeze-drying were established.

In Scotland a sister organisation was formed called the Protein Fractionation Centre (PFC),
which operated until 2006.

The early years

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. Further work in the development of blood products took place in the 1950s
when 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 provided.

In another key development a group led by Pool discovered, in 1959, 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.

Fractionation also allowed the amount of Factor VIII to be concentrated to over 400 times the
natural concentration found in blood plasma. BPL thus created the worlds first clinically
effective Factor VIII concentrate prepared for the treatment of haemophilia. By the late 1960s
the process of freeze-drying (lyophilisation) was used to produce, concentrate and preserve
Factor VIII products.

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 1968. Further in relation to
immunoglobulins, it was at BPL that a pioneering radio immunoassay to screen blood for
hepatitis B was developed.

In 1967, the management at BPL decided to open up a second blood products facility, to be
located on a separate site. 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 with a remit to produce special products for the treatment of
rare forms of haemophilia. The Oxford laboratories were a highly innovative research centre;
for example, PFL developed the first heat treatment process for Factors VIII and IX in the
mid-1980s. PFL continued to operate as BPLs research centre until its closure in 1992. On
closure the laboratorys operations and staff were transferred to BPL.

The 1970s and 1980s

Initially technological limitations concerning the amount of plasma that could be transfused
limited the scale of the production of blood products. However, by the 1970s, increased
capital investment and development of the manufacturing operation akin to that of a
pharmaceutical company pushed forward blood products production in the U.K.
considerably.

The early 1970s saw a greater awareness of blood borne viruses. In response, BPL introduced
screening for hepatitis B in donated plasma in November 1971.

In 1973 the Department of Health decided to convene an expert group to assess the possible
future requirements for the treatment of patients with haemophilia and the consequent need
for the supply of therapeutic agents. The decision was taken was that a substantial increase in
the amount of plasma reaching BPL from the Regional Transfusion Centres (RTCs) for the
preparation of factor VIII was required. However, BPL did not have the capacity to meet this
demand (the combined capacity of BPL and the Plasma Fractionation Laboratory at Oxford
(PFL), in 1977,was said to be 17.5m iu per year).

Plans to expand BPLs production were debated on several occasions in House of Commons
between 1973 and 1976.

Dr David Owen: "As I told my hon Friend the Member for Sowerby on 17
February, I have authorised the allocation of special finance of up to 0.5 million
(about half of which would be recurring) to increase the existing production of
Factor VIII concentrate within the National Health Service with the aim of the
NHS becoming self-sufficient in blood products as soon as possible" (taken from
Hansard).

The 0.5 million was designed to meet a planned increase the output of plasma from
transfusion centres to the equivalent of 275,000 blood donations annually for the preparation
of factor VIII and 100,000 donations for cryoprecipitate.

As indicated earlier, in 1978 financial pressures led to the Lister Institute leaving site, which
was then purchased by the Department of Health, enabling BPLs further development and
expansion. BPL, was transferred from the MRC and became part of the local North West
Thames Health Authority, which took sole control of the site on the 1
st
October that year.
Despite the closure of the institute many maps, to this day, continue mark the location of BPL
as The Lister Institute.

With the ending of the Lister Institute a few arcane practices were abandoned. So went the
practice of scientists and technicians dining in separate canteens and the formal
requirement to address people by their titles. As an interesting benchmark, the average wage
for a laboratory technician at BPL at the time was 25.67 per week.

A political motivation for the BPL expansion of 1978 was criticism of the government by the
medical establishment because Britain was not self-sufficient in blood products and therefore
reliant upon commercial exports to meet forty percent of NHS requirements. (This later
became the subject of an independent public inquiry - the Archer Inquiry 2007-2009). The
goal of self-sufficiency was put in motion by Dr. David Owen, then Minster of Health. A
further driver was because the demand for Factor VIII in England and Wales increased
dramatically in the late 1970s with changes to the dosage regimen for the home treatment of
haemophilia.

In 1980, the British Government agreed to a short-term upgrading of the facilities at BPL at
cost of 1.3million. With this, BPL was expected to double production capacity from 15m iu
pa to 30m iu per year.

In 1981 a change took place to the way that BPL products were distributed in the UK. Blood
products from BPL were initially distributed broadly on the basis of an assessment of
regional requirements for patient treatment. In April 1981 it was agreed that regions should
receive BPL products in quantities proportional to the amount of plasma they had sent to BPL
for processing, account being taken of the yield from each batch of plasma.

The growing strategic and medical importance of BPL led, on 1st December 1982, to the
organisation, along with the International Blood Group Reference Laboratory, being
transferred to a Special Health Authority (SHA) that was created solely to look after blood
products and related matters. The body was called the Central Blood Laboratories Authority
(CBLA), and it was given the remit to:

Oversee the industrial and technology led transition from and NHS laboratory
service, to a fully functional industrial unit (CBLA, 1993: 4).

The CBLA headquarters were located at BPL in a former building called The Crest, which
overlooked the duck pond.

Under the CBLAs guidance, blood products continued to develop through the 1980s. One
significant innovation, as a means to reduce the risk of blood borne virus transmission, was
the heat treatment of Factor VIII (8Y

) and Factor IX. With this process, BPL was a global

innovator with many other plasma fractionators copying the BPL process. 8Y was launched
in 1985 as a (then) new, high purity product which was capable of maintaining satisfactory
yield from fresh frozen plasma, had remarkable in vitro heat stability in the absence of
conventional stabilisers, and had a good record of safety in clinical trials.

In terms of expanding its range of activities, in 1986, BPL set up a new organisation called
the Blood Products Laboratory Diagnostics (BPLD). The aim of the 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.

During the 1980s the footprint occupied by BPL also grew. This opportunity arose when a
nearby aristocratic landowner Sir William Maycock sold his house and grounds (which
included an orchard). This additional space, coupled with increased government investment,
presented an opportunity for the goal of UK self-sufficiency in blood products to be realised.

As a result of government funding, considerable investment (60 million by 1987, against an
original estimate of 21 million) was put into the BPL factory at Elstree. 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, opened by HRH The
Duchess of Gloucester on 29th April 1987, which frames the recognisable wedge-like image
for passers-by. The site and shape of the factory was designed so that met the local green
belt requirements of leafy Hertfordshire.

The new factory became fully operational 1989 and capacity increased from 47,000 litres of
processed plasma in 1976 to 450,000 litres in 1996. The full operation of the factory in 1990
coincided with the governments introduction of an internal (quasi) market into the NHS.

In April 1989 a system of cross-charging was in place. BPL bought plasma from the
National Blood Transfusion Service (reimbursed the RTCs for the cost of providing plasma).
With money previously allocated directly to BPL, blood transfusion centers were then
required to buy the product they needed from BPL

The 1990s
In terms of organisation, throughout the 1980s BPL remained governed by a special health
authority. During this time BPL remained organisationally outside of, but intimately tied to,
the core Blood Service through the receipt of plasma from U.K. blood donors. This
relationship became fully entwined through a merger between BPL and the U.K. Blood
Transfusion Service on 1
st
April 1993 to form the National Blood Authority; and later, in
2005, to form NHS Blood and Transplant following the incorporation of the organ donor
service. This pairing lasted for seventeen years.

In 1991 BPL was re-branded Bio Products Laboratory. The re-branding exercise was
undertaken in tandem with BPLs evolving commercial focus. By the mid-1990s, in order to
meet government set operating cost targets, BPL was granted permission to sell products
above what the NHS required to overseas markets (at this time this was principally Europe,
the Middle East and South America). At the same time the government introduced a charging
mechanism for BPL products to NHS customers (hitherto BPLs products had been
distributed to hospitals for free). All main BPL products became licensed and BPL subject to
medical inspectorate visits. At this stage, BPL had the capacity to meet 75% of the UKs
requirement for coagulation factors; however, the British Government was keen not to restrict
the prescribing choice of clinicians and thus BPL entered a competitive market.

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 and Biological Defence Establishment at Porton Down.

With the development of tests for hepatitis A and B in the 1970s, it became clear that other
types of viral hepatitis, denoted non A non B hepatitis (NANBH), could be transmitted by
blood. By 1991 specially screening tests were in place, based on second-generation assays.
BPL was at the forefront of such testing, setting up a PCR testing facility (which operated
until it was transferred back-out to the blood transfusion service in the late 1990s).

The 1990s saw further developments to the BPL products stream. This included the launch of
high purity coagulation factors, which became braded Replenate

and Replenine

in 1994. It
was also during the 1990s that BPL manufactured its first large volume immunoglobulin.
Initially this was a freeze-dried product called Vigam

-S, made for the first time in 1996 (the

product was later developed in liquid form as Vigam in 1998). The 1990s also saw
improved techniques for viral removal and inactivation. A specially designed area of the
factory the Viral Secure Area (VSA) was established and solvent detergent steps added to
destroy a spectrum of blood borne viruses.

A major impact to BPLs operations, which went onto have a significant impact upon the way
the organisation operates, occurred in 1998. The UK Committee on the Safety of Medicines
(CSM) ruled that UK donated blood was not to be used for the manufacture of blood
products. BPL was instructed to obtain plasma from lower risk sources, principally from
donors in the USA and a further 25 million was spent in order to refit and sanitize the
factory. To safeguard plasma supply for BPL the government purchased, for 48.8 million,
twenty-four US blood banks run by Life Resources Incorporated (LRI) (then trading as
Diagnostics Chemistries Incorporated) in 2003.

Other changes of note related to personnel and infrastructure. The mid-1980s had seen 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 numbers increased to 500 by the late 1990s (and
eventually peaked at 610 in 2010). With infrastructure, further investments into the buildings
took place and dedicated buildings for Engineering, laboratories and R&D were built in the
early 1990s.

The twenty-first century

The twenty-first century saw BPL continue to develop new products, expand its capacity, and
improve patient safety.

With patient safety, the introduction of a solvent detergent process for immunoglobulins from
the year 2000 was a key example of BPLs commitment for biosafety measures. With new
products, a coagulation factor for patients with von Willebrand Disease, (people who need
additional factor VIII for proper blood clotting) and haemophilia A was developed and
launched as Optivate

in 2004. That year also saw the launch of Subgam

, an
immunoglobulin that could be delivered subcutaneously. Following BPLs first FDA
inspection in 2009, an improved intravenous immunoglobulin, Gammaplex

, was launched
and became BPLs first US-marketed product in 2010.

In terms of development and expansion, in January 2011 BPL moved out from the NHS
umbrella and became a stand-alone company under a parent organisation, Plasma Resources
UK. For a short period PRUK was owned by the Department of Health, before the
organisation was sold to Bain Capital Investments in July 2013, with a 20% stake retained by
the Department of Health. With this, BPLs plasma supplier DCI together with BPL
formed one organisation called BPL Holdings.

The new organisation is committed to expanding production and developing filling capacity.
Investment in R&D continues and two unique products were advanced during 2014: Factor X
and Haptoglobin.

Lead by Bain Capital, BPLs new ownership heralds a new and exciting dawn for the
company and its employees and ultimately, for everyone concerned including patients. Bain
Capitals support meant increased investment and the introduction of greater production
levels, which in turn would assure BPLs long-term future as a new organisation and, with
added investment wealth from Bain Capital, ensure that BPL would be able to be committed
to expanding its production, thus fulfilling its vision for years to come.

BPL has become known as a company with an impressive heritage both in setting the
foundations of its history and looking forward, meeting challenging and exciting times ahead
as new and innovative products are developed and released to benefit the needs of partners
and patients around the world who depend, in turn, on the innovations and scientific
perspicuity of its people.

It is with this cherished and stellar heritage that BPL is proud to celebrate its 60 years of
excellence in the development of products designed to meet the needs and to provide the
benefits and the care for the patients and families for whom it has cared and provided for the
world over, during its six decades of passionate service to them all.


References and further reading
British Medical Journal (1978): Freeze Dried Factor VIII Concentrates and the NHS,
British Medical Journal, No. 6237, pp405-406

Brogan, A. H. (1990) Committed to Saving Lives: A History of the Commonwealth Serum
Laboratories, Hyland House, Melbourne, Australia

Chick, H. Hume, M., MacFarlane, M. (1971) War on Disease: a history of the Lister
Institute, London: A. Deutsch

Collier, L.H. (2000) The Lister Institute of Preventive Medicine: a concise history, Lister
Institute of Preventive Medicine, UK

Goldsmith, J.C. (1996): The Coagulation Cascade and Coagulation Factor Replacement in
Hemophilia in Oberman, H.A. (1996): The History of Transfusion Medicine in Petz, L.D.,
Swisher, S.N., Kleinman, S., Spence, R.K. and Strauss, R.G. Clinical Practice of Transfusion
Medicine, 3rd Edition, Churchill Livingstone, New York, pp185-198

Hall, S. (2007): Government knew of HIV risk from imported blood, The Guardian, 25th
May 2007. Guardian Unlimited: http://www.guardian.co.uk/aids/story/0,,2087943,00.html
(accessed 26th May 2007)

Rizza CR, Fletcher ML, Kernoff PB. (1993): Confirmation of viral safety of dry heated factor
VIII concentrate (8Y) prepared by Bio Products Laboratory (BPL): a report on behalf of U.K.
Haemophilia Centre Directors. Br J Haematol. 84(2):269-72

Sandle, T. (2004): 50 Years of providing the Lifeblood of the Nation, Around Radlett,
Aldenham Parish News, No. 63, spring 2004, p5

Swisher, S.N. and Petz, L.D. (1996): Overview and General Principles of Transfusion
Medicine in Petz, L.D., Swisher, S.N., Kleinman, S., Spence, R.K. and Strauss, R.G. Clinical
Practice of Transfusion Medicine, 3rd Edition, Churchill Livingstone, New York, pp1-10

Walker, R. (1999): Team BPL: Response to the impact of nvCJD, Presentation to the NHS
Team of the Year Award, Blood Products Laboratory, Elstree

Ward, J (1997): The cost of blood products to the NHS in Cascade, Strategic Medical
Publishing, Egham, pp6-7

Warden, J. (1998): UK Blood Products are Banned, British Medical Journal, 316, pp723

White, G.C. and Gilbert, G.E. (2003): Coagulation Factors V and VIII: Normal function and
clinical disorders in Hardin. R.I., Lux, S.E. and Stossel, T.P. Blood: Principles and Practice
of Haematology, 2nd Edition, Lippincott-Williams and Wilkins, Philadelphia, pp1195-1248