Manufacturing

Sanofi Genzyme is committed to leading the research, development, and manufacture of treatments for lysosomal storage disorders such as Fabry disease.

Fabrazyme is produced using advanced molecular biologic techniques based on recombinant DNA technology using a CHO (Chinese hamster ovary) mammalian expression system. Sanofi Genzyme has used the methodology extensively since 1994. Fabrazyme manufacturing occurs exclusively at Sanofi Genzyme production facilities.

Early studies of enzyme replacement in the 1970s and 1980s using α-GAL purified from human tissues were promising but practical application was impossible because of the difficulty of obtaining enough purified human enzyme. The advent of genetic engineering and recombinant human DNA technology allowed for production of large-scale quantities of therapeutic proteins such as α-GAL.

Highly Regulated Techniques Help Ensure Reproducibility and Purity

The highly complex, multistep manufacturing process is established, scalable, and rigorously controlled to help ensure consistency and reliability.

Fabrazyme production begins with genetic modification of a host cell to produce α-GAL from human DNA. The CHO cell line was chosen for its well-characterized track record in the manufacture of biopharmaceuticals.

The human α-GAL gene is isolated, spliced into a bacterial plasmid, and then inserted into the CHO host cell, which serves as a hospitable environment to manufacture the protein. In a bioreactor under carefully controlled conditions, the cells grow in a liquid medium of about 50 different nutrients such as sugar, amino acids, and salts. The enzyme is drawn off and collected for purification. The enzyme goes through a multistep purification process, including chromatography and nanofiltration, that is capable of removing virus particles. To help ensure the product meets worldwide regulatory authority standards and specifications, rigorous testing takes place during every stage of the manufacturing process.

The purified α-GAL is stabilized with excipients and undergoes double-sterile filtration before it is filled into vials under aseptic conditions. The vials are lyophilized (freeze-dried to remove oxygen and water) to enhance stability and storage. After lyophilization, vials are ready for final quality-control testing. Each lot of Fabrazyme undergoes an extensive series of quality control tests to confirm consistent quality before being released for patient use.

Protein Manufacture Using Recombinant DNA Technology

The Fabrazyme manufacturing process begins with genetic modification of a host cell to produce human α-GAL. This entails isolating a bacterial plasmid (a small, self-replicating loop of DNA) (step 1), cutting it with a specific enzyme (restriction endonuclease) (step 2), inserting the human α-GAL gene into the plasmid, and “sealing” it up with a different enzyme (DNA ligase) (step 3). The recombinant plasmid is then inserted into a carefully chosen host cell (step 4), which serves as a hospitable environment to manufacture the protein. The protein is then secreted into the culture medium (step 5).

Indication and Usage

Fabrazyme® (agalsidase beta) is indicated for use in patients with Fabry disease. Fabrazyme reduces globotriaosylceramide (GL-3) deposition in capillary endothelium of the kidney and certain other cell types. The reduction of GL-3 inclusions suggests that Fabrazyme may ameliorate disease expression; however, the relationship of GL-3 inclusion reduction to specific clinical manifestations of Fabry disease has not been established.

Important Safety Information

Life-threatening anaphylactic and severe allergic reactions have been observed in patients during Fabrazyme infusions. In clinical trials and postmarketing safety experience, approximately 1% of patients developed anaphylactic or severe allergic reactions during Fabrazyme infusions. Reactions have included localized angioedema (including swelling of the face, mouth, and throat), bronchospasm, hypotension, generalized urticaria, dysphagia, rash, dyspnea, flushing, chest discomfort, pruritus, and nasal congestion. Interventions have included cardiopulmonary resuscitation, oxygen supplementation, IV fluids, hospitalization, and treatment with inhaled beta-adrenergic agonists, antihistamines, epinephrine, and IV corticosteroids. If severe allergic or anaphylactic reactions occur, immediately discontinue administration of Fabrazyme and provide necessary emergency treatment. Because of the potential for severe allergic reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

  • In patients experiencing infusion reactions, pretreatment with an antipyretic and antihistamine is recommended.
  • Infusion reactions occurred in some patients after receiving pretreatment with antipyretics, antihistamines, and oral steroids.
  • If an infusion reaction occurs, decreasing the infusion rate, temporarily stopping the infusion, and/or administrating additional antipyretics, antihistamines, and/or steroids may ameliorate the symptoms.
  • If severe infusion reactions occur, immediate discontinuation of the administration of Fabrazyme should be considered, and appropriate medical treatment should be initiated.
  • Severe reactions are generally managed with administration of antihistamines, corticosteroids, intravenous fluids, and/or oxygen when clinically indicated.
  • Because of the potential for severe infusion reactions, appropriate medical support measures should be readily available when Fabrazyme is administered.

Re-administration of Fabrazyme to patients who have previously experienced severe or serious allergic reactions to Fabrazyme should be done only after careful consideration of the risks and benefits of continued treatment, and only under the direct supervision of qualified personnel and with appropriate medical support measures readily available.

The most common adverse reactions reported are infusion reactions, some of which were severe. Infusion reactions occurred in approximately 50-55% of patients during Fabrazyme administration in clinical trials. Serious and/or frequently occurring (≥ 5% incidence) related adverse reactions consisted of one or more of the following: chills, fever, feeling hot or cold, dyspnea, nausea, flushing, headache, vomiting, paresthesia, fatigue, pruritus, pain in extremity, hypertension, chest pain, throat tightness, abdominal pain, dizziness, tachycardia, nasal congestion, diarrhea, edema peripheral, myalgia, back pain, pallor, bradycardia, urticaria, hypotension, face edema, rash, and somnolence.

  • Patients with advanced Fabry disease may have compromised cardiac function, which may predispose them to a higher risk of severe complications from infusion reactions. Patients with compromised cardiac function should be monitored closely if the decision is made to administer Fabrazyme.
  • Other serious adverse events reported in clinical studies included stroke, pain, ataxia, bradycardia, cardiac arrhythmia, cardiac arrest, decreased cardiac output, vertigo, hypoacousia, and nephrotic syndrome. These adverse events also occur as manifestations of Fabry disease; an alteration in frequency or severity cannot be determined from the small numbers of patients studied.
  • Severe and serious infusion related reactions have been reported in postmarketing experience, some of which were life threatening including anaphylactic shock. In addition to the above adverse reactions, the following have been reported during postmarketing use of Fabrazyme: arthralgia, asthenia, erythema, hyperhidrosis, infusion site reaction, lacrimation increased, leukocytoclastic vasculitis, lymphadenopathy, hypoesthesia, oral hypoesthesia, palpitations, rhinorrhea, oxygen saturation decreased and hypoxia.
  • Adverse reactions (regardless of relationship) resulting in death reported in the postmarketing setting with Fabrazyme treatment included cardiorespiratory arrest, respiratory failure, cardiac failure, sepsis, cerebrovascular accident, myocardial infarction, renal failure, and pneumonia. Some of these reactions were reported in Fabry disease patients with significant underlying disease.

The safety and efficacy in patients younger than 8 years of age have not been evaluated.

Most patients who develop IgG antibodies do so within the first three months of exposure. IgG seroconversion in pediatric patients was associated with prolonged half-life of Fabrazyme, a phenomenon rarely observed in adult patients.

In clinical trials, a few patients developed IgE or skin test reactivity specific to Fabrazyme. Physicians should consider testing for IgE in patients who experienced suspected allergic reactions and consider the risks and benefits of continued treatment in patients with anti-Fabrazyme IgE antibodies.

Fabrazyme is available by prescription only. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/safety/medwatch or call 1‑800‑FDA‑1088. You may also contact Sanofi Genzyme at 1-800-745-4447, option 2. To learn more, please see the full prescribing information (PDF) or contact Sanofi Genzyme at 1-800-745-4447.