Glyko Biomedical Ltd.'s 30.6%-owned affiliate, BioMarin Completes Important Milestone in the Manufacturing of Aldurazyme.Business/Health Editors
NOVATO Novato (nōvä`tō), residential city (1990 pop. 47,585), Marin co., W Calif., N of San Fransisco on San Pablo Bay; inc. 1960. In a farming and dairying area, it produces cosmetics, metal products, telephone apparatus, lumber, and wiring , Calif.--(BW HealthWire)--April 24, 2001
BioMarin Senior Management Provides Comprehensive
Glyko Biomedical bi·o·med·i·cal
1. Of or relating to biomedicine.
2. Of, relating to, or involving biological, medical, and physical sciences. Ltd.'s (OTCBB OTCBB
See OTC Bulletin Board (OTCBB). : GLYK; TSE See Tokyo Stock Exchange.
1. See Tokyo Stock Exchange (TSE).
2. See Toronto Stock Exchange (TSE). : GBL GBL Gamma-Butyrolactone
GBL government bill of lading (US DoD)
GBL Ground-Based Laser
GBL Game Boy Light
GBL General Bearing Line
GBL Generation Breakdown List
GBL Ground-Based Laboratory
GBL Green Bus Lines, Inc. ; BVD-Berlin: GLY Gly glycine.
glycine. ) 30.6%-owned affiliate, BioMarin Pharmaceutical BioMarin Pharmaceutical (NASDAQ: BMRN) is a biotechnology firm based in Novato, California. It has offices and facilities in both the US and Europe. BioMarin's core business and research is in enzyme replacement therapies. Inc. (Nasdaq and Swiss SWX SWX Swiss Exchange (trademark of SWX Swiss Exchange)
SWX SolidWorks (3D solid modeling CAD software)
SWX Splitter / Wave Division Multiplexer New Market: BMRN) announced today that it has completed the last major manufacturing milestone for Aldurazyme(TM) prior to the submission of a Biologics Biologics include a wide range of medicinal products such as vaccines, blood and blood components, allergenics, somatic cells, gene therapy, tissues, and recombinant therapeutic proteins. License Application (BLA BLA
Bachelor of Liberal Arts ) in the U.S. and Marketing Authorization The right or permission to use a system resource; the process of granting access. See access control. Application (MAA MAA
macroaggregated albumin ) in Europe Europe (yr`əp), 6th largest continent, c.4,000,000 sq mi (10,360,000 sq km) including adjacent islands (1992 est. pop. 512,000,000). . This key step involved the manufacture of the five required process qualification lots of Aldurazyme. Three process qualification lots are required for the submission of a BLA to the U.S. FDA FDA
Food and Drug Administration
n.pr See Food and Drug Administration.
n.pr the abbreviation for the Food and Drug Administration. , and five lots are required for the submission of an MAA to the European European
emanating from or pertaining to Europe.
European bat lyssavirus
European beech tree
see cryptococcosis. regulatory authorities Noun 1. regulatory authority - a governmental agency that regulates businesses in the public interest
administrative body, administrative unit - a unit with administrative responsibilities .
Aldurazyme, recombinant recombinant /re·com·bi·nant/ (re-kom´bi-nant)
1. the new entity (e.g., gene, protein, cell, individual) that results from genetic recombination.
2. pertaining or relating to such an entity. See also under DNA. human alpha-L-iduronidase alpha-L-iduronidase
deficiency of the enzyme considered to be counterpart of mucopolysaccharidosis in cats and dogs; a neuronal storage disease. , is being tested in a Phase III Noun 1. phase III - a large clinical trial of a treatment or drug that in phase I and phase II has been shown to be efficacious with tolerable side effects; after successful conclusion of these clinical trials it will receive formal approval from the FDA pivotal trial with BioMarin's joint venture partner Genzyme Genzyme Corporation (NASDAQ: GENZ) is a biotechnology company based in Cambridge, Massachusetts. Genzyme is the world’s third biggest biotechnology company employing over 9,000 people around the world. General (Nasdaq: GENZ) as enzyme replacement therapy Enzyme replacement therapy is a medical treatment replacing an enzyme in patients in whom that particular enzyme is deficient or absent. Usually this is done by giving the patient an intravenous (IV) infusion containing the enzyme. for patients with MPS-I, a debilitating de·bil·i·tat·ing
Causing a loss of strength or energy.
Weakening, or reducing the strength of.
Mentioned in: Stress Reduction , life-threatening genetic disease.
Raymond W. (Bill) Anderson Anderson, river, Canada
Anderson, river, c.465 mi (750 km) long, rising in several lakes in N central Northwest Territories, Canada. It meanders north and west before receiving the Carnwath River and flowing north to Liverpool Bay, an arm of the Arctic , BioMarin's Chief Operating and Chief Financial Officer, said, "Progress at our cGMP cGMP
3'5' cyclic guanosine monophosphate; essential in regulation of sodium channels of the retina. Decrease in cGMP concentration leads to hyperpolarization of the retinal membrane. commercial manufacturing facility has exceeded our expectations with regard to the amount, quality, and reduced cost of formulated for·mu·late
tr.v. for·mu·lat·ed, for·mu·lat·ing, for·mu·lates
a. To state as or reduce to a formula.
b. To express in systematic terms or concepts.
c. bulk enzyme enzyme, biological catalyst. The term enzyme comes from zymosis, the Greek word for fermentation, a process accomplished by yeast cells and long known to the brewing industry, which occupied the attention of many 19th-century chemists. produced for the Aldurazyme development program. With improvements developed by our Process Development group, we increased productivity by a factor greater than four and reduced costs proportionately pro·por·tion·ate
Being in due proportion; proportional.
tr.v. pro·por·tion·at·ed, pro·por·tion·at·ing, pro·por·tion·ates
To make proportionate. . At the same time, we have completed validation See validate.
validation - The stage in the software life-cycle at the end of the development process where software is evaluated to ensure that it complies with the requirements. studies that, combined with a rigorous quality system, help ensure product and process quality. As a result, we are confident that we will be able to meet the commercial demand for Aldurazyme."
John L. Jost, Ph.D., BioMarin's Vice President, Manufacturing, added, "We have developed an efficient manufacturing process in which the enzyme is properly glycosylated and phosphorylated. This enables us to produce Aldurazyme that has therapeutic effects (as reported by the New England Journal of Medicine The New England Journal of Medicine (New Engl J Med or NEJM) is an English-language peer-reviewed medical journal published by the Massachusetts Medical Society. It is one of the most popular and widely-read peer-reviewed general medical journals in the world. , January 18, 2001) at a dose of only 0.7 mg per kg of patient weight per week - approximately one and a quarter grams per average patient per year. The reason for this low dose is that the enzyme produced by our Chinese Hamster The Chinese Hamster is a species of hamster, scientific names Cricetulus griseus, which originates in the deserts of northern China and Mongolia. These animals grow to between 7.5 and 9 cm in length and as adults can weigh 50-75 grams. Ovary ovary, ductless gland of the female in which the ova (female reproductive cells) are produced. In vertebrate animals the ovary also secretes the sex hormones estrogen and progesterone, which control the development of the sexual organs and the secondary sexual (CHO CHO Carbohydrate (chemical formla Carbon Hydrogen Oxygen)
CHO Chinese Hamster Ovary
CHO Chemical Hygiene Officer
CHO Chief Health Officer (corporate title) ) cell line has the proper structure of mannose-6-phosphate (M-6-P) ligand ligand (lĭg`ənd), charged or uncharged molecule with one or more unshared pairs of electrons that can attach to a central metallic atom or ion to form an aggregate known as a complex ion (see chemical bond). needed to ensure efficient uptake uptake /up·take/ (up´tak) absorption and incorporation of a substance by living tissue.
n. by the M-6-P receptors that are present on all of each patient's cells. Our CHO cells directly produce recombinant human alpha-L-iduronidase without the complexities inherent in additional manufacturing steps to remodel re·mod·el
tr.v. re·mod·eled also re·mod·elled, re·mod·el·ing also re·mod·el·ling, re·mod·els also re·mod·els
To make over in structure or style; reconstruct. the enzyme."
Frequently Asked Questions About Manufacturing at BioMarin
"As a relatively young company, members of the investment community frequently ask us about our manufacturing capabilities," Mr. Anderson Mr. Anderson can refer to several fictional characters:
Glyko Biomedical Ltd.'s principal asset is a 30.6% ownership in the capital stock of BioMarin Pharmaceutical Inc.
BioMarin specializes in the development and commercialization of therapeutic enzyme products. Since inception in 1997, BioMarin has applied its proprietary enzyme technology to develop products for lysosomal storage diseases lysosomal storage diseases A heterogeneous group of diseases with specific lysosomal enzyme defects. Cf Inborn errors of metabolism. and for the treatment of serious burns. Glyko, Inc., a BioMarin subsidiary, provides analytical analytical, analytic
pertaining to or emanating from analysis.
control of confounding by analysis of the results of a trial or test. and diagnostic products and services in the area of carbohydrate carbohydrate, any member of a large class of chemical compounds that includes sugars, starches, cellulose, and related compounds. These compounds are produced naturally by green plants from carbon dioxide and water (see photosynthesis). biology.
This press release contains forward-looking statements forward-looking statement
A projected financial statement based on management expectations. A forward-looking statement involves risks with regard to the accuracy of assumptions underlying the projections. about the business prospects of BioMarin Pharmaceutical Inc., including the following potential future products: Aldurazyme for MPS-I and rhASB for MPS-VI. Results may differ materially depending on the progress of BioMarin's product programs, actions of regulatory authorities, availability of capital, future actions in the pharmaceutical market and developments by competitors, and those factors detailed in BioMarin's filings with the Securities and Exchange Commission such as 10Q, 10K and 8K reports.
Aldurazyme(TM) is a trademark of BioMarin/Genzyme LLC (Logical Link Control) See "LANs" under data link protocol.
LLC - Logical Link Control , which was formed in 1998 to develop and commercialize Aldurazyme throughout the world.
BioMarin's releases and other information on the Company and its products and technologies are available on the World Wide Web at: http://www.BioMarinPharm.com.
Biographies of Mr. Anderson, Dr. Jost, and Dr. Baffi can be found on the World Wide Web at: http://www.BioMarinPharm.com/about/management.html.
BioMarin Pharmaceutical Inc. Frequently Asked Manufacturing Questions and Answers 1) Q - Where will BioMarin manufacture commercial lots of Aldurazyme, the Company's enzyme product being developed for patients with MPS-I? A - Mr. Anderson -"BioMarin's manufacturing facility for commercial production is its `Galli Drive' facility located in Novato, California. The facility is designed for the commercial production of Aldurazyme (alpha-L-iduronidase) for use in enzyme replacement therapy for MPS-I. It produced the bulk enzyme for our pivotal Phase III trial that will be concluded later this year. The production technology used is recombinant CHO cell culture using a perfusion process. The Galli drive facility currently has approximately 900 liters of bioreactor cell culture capacity. The plant has protein purification capacity utilizing column chromatographic methods widely used in the biotechnology industry. The plant produces formulated bulk enzyme. The bulk enzyme is then shipped to our partner Genzyme or to an experienced contract manufacturer where it is filled into vials, labeled, and packaged for distribution." 2) Q - What is the physical size of the Galli Drive facility and what is the investment necessary to support Aldurazyme commercial production? A - Mr. Anderson - "The current configuration of the manufacturing operations (including related quality assurance and quality control functions) occupies approximately 51,800 square feet. Of this total floor space, the developed areas include 12,500 square feet of cGMP (current Good Manufacturing Practice) process manufacturing areas, 2,200 square feet of quality control laboratories, 8,000 square feet of materials and warehouse and 29,100 square feet of utilities support area and manufacturing-related administrative areas. When current facility modifications are completed in Q4 2001, BioMarin will have invested $28 to $30 million in the manufacturing areas of the facility." 3) Q - What is the capacity of the Galli Drive facility in terms of Aldurazyme market requirements? A - Mr. Anderson - "Based on our current production experience (without future process improvements), the facility can produce bulk enzyme sufficient for the treatment of approximately 2,400 patients per year. This capacity represents 70% of the 3,400 patients estimated to be available in the economically developed world, which is the primary market for Aldurazyme. At this level of output, the facility would be sufficient to satisfy the expected market demand for several years post approval." 4) Q - What manufacturing regulatory steps are necessary prior to launch of Aldurazyme? A - Dr. Baffi - "The Galli Drive facility was constructed in 1999, and full effort on the preparation and start-up of cGMP operations began in January 2000. The facility was licensed for the production of product for use in clinical trials by the California Food and Drug Branch in June 2000. Under cGMP procedures and disciplines, we completed production of clinical enzyme sufficient for the Phase III clinical trial of Aldurazyme in September 2000. In the production `campaign' that began in October 2000 and that is scheduled to end in May 2001, we have completed five Process Qualification (PQ) runs and will complete three additional runs for validation studies. Three PQ runs are required for the U.S. BLA submission and five PQ runs are required for the European MAA submission. We anticipate that the U.S. FDA will inspect the facility in a Pre-Approval Inspection (PAI) about two months after the filing of the BLA, and the European regulatory authorities will conduct their separate inspection approximately six months after the filing of the MAA. The preparation for both inspections is a major activity for the facility staff in the second half of 2001 and early 2002. The current staff, which is sized for cGMP production operations at schedules anticipated to be required for the near term, includes 73 professionals. "We are now conducting real time and accelerated stability studies in compliance with the International Conference on Harmonization (ICH) guidelines. Based on results to date, we are planning on dating of 18 to 24 months for final product." 5) Q - What level of success has BioMarin had with the Aldurazyme process to date? A - Dr. Jost - "The current process for the production of Aldurazyme yields enzyme with purity levels that meet or exceed industry standards for injectable proteins. The process to date has proven to be both robust and repeatable. For planning purposes, the Company's long-term capacity projections assume a manufacturing run success rate of 70%. However, the recent manufacturing run success rate is greater than 90%. With the complexity and variability inherent in biological processes, this is a highly positive result. "Most important, the production output in terms of vial equivalents per run in the current campaign has increased by a factor of at least four from earlier start-up runs and from our earlier projections. Like all active processes in early stages, we have a number of promising process development initiatives which we will be investigating to further improve production yields." 6) Q - What is the current status of quality systems for Aldurazyme? A - Dr. Baffi - "Over the last year, we have greatly strengthened the systems that are required to certify the product quality of Aldurazyme. We have developed and are validating a series of 19 assays to support product quality. The quality system is consistent with the leading industry standards and practices in the quality area in that it is considered to be `orthogonal' (that is, it measures different independent product characteristics in multiple, different product `dimensions'.) Upon completion of the last validation runs in May, the required validation studies and the quality systems will be in place for the Pre-Approval Inspections." 7) Q - What is the significance of the fact that Aldurazyme is properly glycosylated and phosphorylated? A - Dr. Jost - "Aldurazyme is administered at a dose of 0.7 mg per kg of patient weight per week and, as a result, a standard patient requires a total dose of about one and a quarter grams per year. Our weekly dose is approximately equal to the total body content (the calculated amount of enzyme present) in a healthy person of the same size. The reason for this low dose is that the enzyme produced by our CHO (Chinese Hamster Ovary) cell line has the proper structure and is properly glycosylated and phosphorylated. Specifically, the enzyme has sufficient quantities of mannose-6-phosphate (M-6-P) ligand to ensure efficient uptake by the patient's cells. Our CHO cell lines directly produce recombinant human alpha-L-iduronidase without the complexities inherent in additional manufacturing steps to remodel the enzyme. "Our manufacturing process has been validated to deliver Aldurazyme that is consistently and properly glycosylated and phosphorylated. This simple and direct process promises lower costs than the much more complex processes that may add extra M-6-P ligands. The well-known relationship between the cell surface receptor and the M-6-P ligand suggests that additional M-6-P ligands will not improve cellular uptake. In addition, extra M-6-P ligands may result in immunogenicity concerns and unanticipated side effects. Based on pharmacokinetic studies in MPS-I canines and in MPS-I human patients, Aldurazyme levels achieved in the bloodstream are saturating the M-6-P receptors on cells. Further increases in phosphorylation above the current level will not improve tissue uptake of the enzyme. "Our primary activity test for Aldurazyme is an assay that measures the uptake of Aldurazyme by human fibroblast cells isolated from an MPS-I patient. This `biomimetic' assay (direct measure of a key biological function) is consistent with the proposed mechanism of action of Aldurazyme and is considered to be a very predictive test of both enzymatic activity and proper glycosylation and phosphorylation. Multiple analytical methods are employed to assess product quality and consistency. Five of the eight assays that evaluate the structural integrity of Aldurazyme are sensitive to the quantity of glycosylation and phosphorylation." 8) Q - Have you had problems developing Aldurazyme and bringing it into production? A - Dr. Jost - "We have had no extraordinary difficulties in developing and producing Aldurazyme, but the multitude and breadth of the tasks required to be completed in parallel was challenging. In approximately nine months of 2000, we brought into operation a cGMP compliant new facility, closed and transferred the staff from a pilot facility, implemented an improved production process, developed a more stable formulation, began cGMP operations, made sufficient clinical product to enable and complete the Phase III trial, and improved per run output significantly. "By May, we will have completed eight successful, Process Qualification/validation runs that will supply all of our clinical product needs up to the time of the projected commercial launch with additional product available for the launch." 9) Q - What were the circumstances and decisions surrounding the closing of the Carson Street clinical facility in Torrance, California, from which the original Aldurazyme clinical materials were produced? A - Dr. Jost - "The location of the Carson Street facility was selected to be close to the Harbor-UCLA REI laboratory where Aldurazyme was originally produced for both preclinical requirements and the Phase I clinical trial. The Carson Street plant was prepared to meet the initial production needs for Aldurazyme while a second cGMP plant at Galli Drive was developed, but, being a smaller plant, the production capacity of the Carson Street facility could not reach the levels that were desired for an efficient commercial launch. When the Galli Drive facility came on line, the Carson Street facility was closed to improve operational efficiency. "We completed the last runs required from the Carson Street facility at the end of April 2000 and closed the facility. We were pleased that 16 of the 25 technical staff working at Carson Street transferred to our Galli Drive facility, thus contributing their experience in the production of the enzyme to the new facility." 10) Q - What is BioMarin's current manufacturing facility for the production of rhASB for MPS-VI? A - Dr. Jost - "We currently produce bulk rhASB for clinical trials in a clinical manufacturing facility in our Bel Marin Keys Boulevard (`BMK') facility in Novato, California. Specialized fill/finish operations are done by an experienced contract fill/finish manufacturer. The production technology is recombinant CHO cell culture. For cell culture using a perfusion process, the facility will operate at the 110-liter scale. The facility has protein purification capacity that is balanced with the cell culture capacity. The primary method of protein purification is column chromatography. In June 2000, the BMK facility was licensed by the California Food and Drug Branch for the production of clinical product." 11) Q - What is the size of and the investment in the BMK facility? A - Mr. Anderson - "The BMK manufacturing operations occupy approximately 2,700 square feet, of which, 1,500 square feet is for cGMP manufacturing process areas, 700 square feet is for materials, and 500 square feet is for utilities support and manufacturing-related administration. When current modifications are completed in July 2001, BioMarin will have invested approximately $1.9 million in the clinical manufacturing areas of the BMK facility." 12) Q - What is the capacity of the BMK facility as it relates to producing rhASB clinical materials? A - Dr. Jost - "We have already made sufficient amounts of rhASB to complete the Phase I clinical trial including enough to maintain the patients on the drug after the evaluation part of the trial is completed this summer. In addition, after facility modifications, the capacity will be sufficient for Phase II and potentially even Phase III clinical trials of rhASB for MPS-VI." 13) Q - What is the current status of the production process for rhASB? A - Dr. Jost - "The productivity of the process using recombinant DNA techniques in a CHO host cell line is sufficient to support clinical trials. Our assays indicate that rhASB is properly glycosylated and phosphorylated (has the proper structure of M-6-P ligands) for efficient uptake. With experience gained from the Aldurazyme purification process, we now have an improved purification process for rhASB with higher net yields and lower volumes of material to be handled. In the BMK operation, we have also recorded a very favorable production run success rate of greater than 90%. From early results of stability studies in progress, we anticipate product dating for rhASB that is similar to that projected for Aldurazyme."