Subject: PR: How to make Beta/Beta availability

From: "Ross M. Greenberg" <[email-masked]>
Date: Wed, 28 Sep 1994 12:42:00 EST

This is PR. As such, don't trust it without independent verification.

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OTC  09/23 1624  BETASERON (INTERFERON BETA-1B) FOR SC INJECTION ...

 WAYNE, N.J., Sept. 23 /PRNewswire/ -- Research is only the first step in the
development of new therapeutic agents.  To convert scientific research into
widely available products, companies must move from the research setting to
commercial scale production.  For production of the most complicated molecules,
this step can often limit or delay the widespread availability of new products.
   Nowhere in pharmaceutical manufacturing has this proven more challenging
than for the production of complex and sophisticated compounds created through
the recombinant DNA techniques of genetic engineering.
   More akin to cultivation than traditional pharmaceutical production, the
recombinant drug manufacturing process turns bacteria into tiny biological
factories.  These bacteria, known as altered Escherichia coli (E. coli), are
organisms that require special care.  To make commercial quantities of a
recombinant DNA product recombinant E. coli are modified by inserting the gene
needed for production of the desired protein.  The bacteria continue to survive
and reproduce themselves and in doing so, produce the desired protein. For
commercial quantities, large volumes of these genetically identical (modified)
bacteria must be produced in very carefully controlled conditions.

     Betaseron(R) (Interferon beta-1b) for SC Injection
     Chiron Corporation uses this process to produce Betaseron(R) (Interferon
beta-1b) for SC Injection, a drug recently licensed for use in ambulatory
patients with relapsing-remitting multiple sclerosis (MS) to reduce the
frequency of exacerbations.
   In developing Betaseron(R), scientists isolated the specific human gene that
naturally produces the protein, interferon beta.  Then in a sophisticated
laboratory process, scientists manipulated the gene in such a way that it would
produce a more stable protein.  This process substituted a serine residue at
the 17th position in the protein's amino acid chain.  The result was a protein
that retained the biological structure similar to natural human interferon
beta, but had improved stability.

     The Manufacturing Process
     The first major step in producing commercial quantities of Betaseron(R) is
known as fermentation.  During fermentation, a small volume of genetically
manipulated cells are placed into a large volume of growth media.  It is during
this time that the bacteria grows and produces the necessary proteins.  This
occurs in a large scale fermentation vessel.
   The bacteria are allowed to reproduce until they have multiplied about 20
times their original population.  The bacteria are then "turned on" by chemical
induction, a process that can be likened to a chemical light switch.  This
"turn on" allows the bacteria to start producing the interferon beta and the
cell population is doubled again; fermentation concludes with a population
about 40 times its original size.
   Separation of the interferon protein from other cellular materials is the
next step in the manufacturing process.  To do this, the entire fermentation
batch is homogenized in a process similar to blending a milkshake.  The
majority of the cell debris is then removed from the interferon by
centrifugation, which leaves a liquid portion containing the interferon.
Further centrifugation allows the solution to be separated by weight into
different layers of proteins; as a result, interferon can be separated from
many of the non-interferon proteins produced by the E. coli.  The relatively
pure interferon is then concentrated in preparation for a second separation.

     Further Purification
     A second separation removes any remaining  proteins from the interferon.
This process, called size exclusion chromatography, produces an ultra-pure,
highly potent protein.  To prepare interferon beta for use in the clinic, the
protein is then formulated and stabilized.
   Stability is established by stopping the protein's chemical changes through
addition of specific ingredients.  If this preventive step were not taken the
protein could fall apart, or change its form, leaving a protein that would not
act like interferon when it was administered to a patient.  Human serum
albumin, a naturally occurring protein used commonly in medicine and dextrose,
a highly purified sugar, are added during the formulation of Betaseron(R)
(Interferon beta-lb) for SC Injection.
   The stabilized Betaseron(R) is then put into vials under strictly sterile
conditions.  Once in the vials, the liquid is freeze-dried to remove the water;
this step further stabilizes the protein, allowing for extended and convenient
storage.  Before Betaseron(R) can be used by a patient, it must be
reconstituted with a special saline solution designed to mimic the body's
natural salt balance.  This reconstitution allows the protein formulation to
return to its liquid state and facilitates absorption of the interferon by the
human body.

     Manufacturing Improvements
     While supplies of Betaseron(R) (Interferon beta-1b) for SC Injection were
limited when the product first became available, Berlex Laboratories, the
developer and marketer of the product, has been able to offer Betaseron(R) to
all patients currently registered on its access list to receive therapy.  As a
result of intensive efforts on the part of Chiron Corporation, Berlex's
manufacturing partner for Betaseron(R), new equipment and expanded facilities
for the production of this product are now in place.
   Most significantly, Chiron will be producing Betaseron(R) in a new, smaller
vial.  While the product formulation and dosage remains unchanged, this
smaller-sized vial allows more vials to be processed simultaneously, thus
accelerating the manufacturing process.

     Quality Assurance
     At each and every stage of the production process, the product must meet
stringent specifications.  If, for any reason, these specifications are not met
that particular batch must be discarded.  This is a time-consuming, but
essential safeguard to ensure the products safety and efficacy.
   -0-                  9/23/94 /CONTACT:  Wendy Neininger of Berlex
Laboratories, 201-292-8043; Larry Kurtz of Chiron Corporation, 510-601-2476; or
Joe Richardson, or Julia Davis, both of Burson-Marsteller, 212-614-5263, or
212-614-4196/
  CO:  Berlex Laboratories; Chiron Corporation ST:  New Jersey IN:  MTC SU:

- --
Ross M. Greenberg       Virus Acres                  914-586-2023
[email-masked]     New Kingston, NY 12459  Fax: 914-586-2025

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