04 juillet 2009
Conseils préparés par le groupe de travail de l'Union Européenne Cerezyme : Conseils à la Communauté "Gaucher" sur la Gestion d
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Ghislaine SURREL
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Guidance to the Gaucher Community on the
Management of Cerezyme Supply
Temporary Conservation of Cerezyme Supply to
Protect the Most Vulnerable Patients with Gaucher Disease
Guidance prepared by the EU Cerezyme Stakeholders Working Group, 24 June 2009
Jeremy Manuel
EGA Board Member
Yossi Cohen
EGA Board Member
Nadia Belmatoug, MD
Beaujon Hospital, Clichy, Ass.Publique-Hôpitaux de Paris, France
Maria Domenica Cappellini, MD
Milan University, Italy
Patrick Deegan, MD
Addenbrooke's Hospital, Cambridge, UK
Eugen Mengel, MD
Children’s Hospital, Gutenberg+University, Mainz, Germany
Anna Tylki-Szymanska, MD
Children’s Memorial Health Institute, Warsaw, Poland
Ashok Vellodi, MD
Great Ormond Street Hospital, London, UK
Ari Zimran, MD
Shaare Zedek Medical Center, Jerusalem, Israel
Susan Graham, MD
Global Medical Affairs, Gaucher disease, Genzyme Europe BV
Oved Amitay
VP, General Manager, Gaucher Disease Portfolio, Genzyme Corporation
Stephanie Hoffmann
Associate Director, Patient Group Relations, Genzyme Europe BV
Barbara Diana
Associate Product Manager, Genzyme Europe BV
*Please note that some individuals who participated in the Cerezyme Stakeholders Working Group are employees of Genzyme and other individuals or their institutions or organizations receive or have received funding from Genzyme for research, educational activities, and other purposes.
Background
Genzyme recently identified a virus (vesivirus 2117) in one of six bioreactors at its Allston manufacturing facility. This virus is not known to cause disease in humans, but it can impair the viability of the non-human CHO cells used to produce Cerezyme. Genzyme has temporarily suspended the production of Cerezyme® (imiglucerase) in order to sanitize this facility and to restore full production as quickly as possible. This manufacturing interruption will result in a temporary shortage in the supply of Cerezyme.
Additional lots of Cerezyme produced at the Allston facility have been tested for the presence of vesivirus 2117. No evidence of this virus has been detected. Based on this information, the FDA and EMEA authorized Genzyme to begin shipping the Cerezyme in inventory that had completed testing. Genzyme continues to work with the FDA and EMEA to test additional lots of Cerezyme that have not yet been released.
However, even with the release of this additional inventory, Genzyme still anticipates a supply shortage for Cerezyme. If no changes are made in the current patterns of Cerezyme use, the available supply is expected to “stock-out” at the end of July 2009 and the shortage would be expected to continue until mid-September or early October 2009 when additional Cerezyme becomes available following the restart of production (a stock-out period of approximately 6 – 8 weeks, based on current assumptions)
Gaucher disease is heterogeneous in its clinical manifestations and progression. A temporary interruption of Cerezyme treatment could have adverse health consequences for some of the most vulnerable patients. For this reason, a plan is needed to protect the most vulnerable patients by allowing them to continue treatment with Cerezyme at their current dosing regimen throughout the period of supply shortage.
In order to accomplish this objective, a Cerezyme Stakeholders Working Group was convened to develop and disseminate guidance recommendations to temporarily decrease the amount of Cerezyme used by the less vulnerable patients so that the conserved supply could be used to protect the most vulnerable patients until an adequate supply of Cerezyme is restored.
The Stakeholders Working Group includes a group of internationally-recognized physicians with deep clinical and scientific expertise in managing Gaucher disease. These physicians are not experts in virology and do not have an in depth knowledge of the manufacturing process of Cerezyme. The Stakeholders working group also included the European Gaucher Alliance (EGA) and representatives from Medical Affairs, Marketing and Patient Advocacy at Genzyme Europe BV (who provided background information and coordinated the meeting).
The Cerezyme Stakeholders Working Group embraced several principles in developing this guidance for temporary conservation of Cerezyme supply:
• The guidance should be designed to protect the most vulnerable patients.
• The guidance should be designed to minimize any risk for all other patients.
• The guidance should be the same irrespective of commercial or charitable access status.
• The guidance should be based on the best available evidence and experience.
• The guidance should aim for wide dissemination and compliance.
• The guidance should be simple to understand and practical to implement.
• Physicians should always make the final treatment decisions regarding their patient
Recommendations
The Cerezyme Stakeholders Working Group met via web conference on 24 June 2009 to address the following objectives:
1. Review and clarify, where appropriate, the EMEA recommendations to physicians concerning the management of the most vulnerable patients, whose Cerezyme treatment should not be interrupted
2. Review and clarify, where appropriate, the recommendations for temporary reductions in Cerezyme dosing or frequency of infusions for all other Gaucher patients
3. Discuss, refine and disseminate the EMEA recommendations for the Gaucher community on the management of Cerezyme supply during the period of temporary shortage
This guidance is based on the assumption that these recommendations should be applied only on a temporary, short-term basis, effective immediately, until the period of Cerezyme shortage ends.
EMEA DHCP Recommendations
Most vulnerable patients
a. Infants, children and adolescents should receive Cerezyme at the approved dose and infusion frequency, because these “early-onset patients” have the most rapid disease progression and are at risk of serious long-term problems
b. Adult patients with active disease progression (eg. pulmonary hypertension, active skeletal disease, severe thrombocytopenia or severe anaemia) should receive Cerezyme at the approved dose and infusion frequenc
Additional comments to the recommendations:
1. Pregnant women, type III patients, Gaucher patients with malignancy who are currently receiving Cerezyme should continue according to their current dose and frequency, without any interruptions
2. Gaucher patients who become pregnant and would benefit from treatment should be advised to consider commencing therapy
3. Newly diagnosed patients who meet the criteria for group (a) or (b) above, are recommended to initiate treatment with Cerezyme promptly.
Active skeletal disease is described as skeletal disease likely to benefit from treatment and ongoing symptoms, such as bone pain, ameliorated by treatment.
Physicians should always make the final treatment decisions regarding their patients on an individual basis.
EMEA DHCP Recommendations
Less vulnerable patients
a. Adult patients without clinical evidence of active disease progression should receive Cerezyme at a reduced dose (e.g. 50% dose once every two weeks) or at a reduced infusion frequency (e.g. once a month at their current dose).
b. No patient should be treated at a dose lower than 15 Units/kg every 2 weeks.
c. Active follow-up in this group should include monitoring of haemoglobin, platelets and chitotriosidase levels, as appropriate, at baseline and bimonthly.
Additional comments to the recommendations:
1. Stable adult patients who have been receiving Cerezyme treatment for ≥2 years could be considered for treatment interruptions for up to 3 months. During this period these patients should be monitored as deemed appropriate by the treating physician in partnership with the patient.
2. Dosing is frequently individualized and if deemed appropriate by the treating physician, doses below 15U/kg bi-weekly can be prescribed, if patients are already stable on these doses.
3. Newly diagnosed patients who do not meet the criteria for “most vulnerable patients” should defer initiating treatment with Cerezyme until the period of Cerezyme shortage has ended.
Any patient who has had a change in treatment regimen should be advised to seek advice from their treating physician should they suffer from Gaucher related symptoms (e.g. weakness, fatigue, abnormal bruising).
Physicians should always make the final treatment decisions regarding their patients on an individual basis.
General Guidance
a. The recommendations and guidelines should be implemented immediately and widely in order to conserve an adequate supply of Cerezyme for the most vulnerable patients.
b. The recommendations and guidelines should be implemented irrespective of commercial or charitable access status.
c. The recommendations and guidelines should be continued until notification by Genzyme that adequate supply has been restored.
d. At the end of this temporary period of Cerezyme shortage, it is recommended that all patients should resume their previously prescribed dosage regimen.
e. The recommendations may be subject to change if the guidance is not widely adopted or if Cerezyme production timelines need to be revised.
ICGG Gaucher Registry
Those physicians (and their patients) who are enrolled in the ICGG Gaucher Registry are encouraged to enter the clinical data collected during the shortage period and thereafter.
Adverse Events
Adverse events for Cerezyme should be reported to the pharmacovigillance department at Genzyme. Physicians are reminded to document batch numbers in the patient records.
26 juin 2009
EMEA 25-06-09 : Problèmes d'approvisionnement de Cerezyme et Fabrazyme suite contamination d'1 réacteur (virus Vesivirus 2117)
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Ghislaine SURREL
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European Medicines Agency
Press office
London, 25 June 2009
Doc. Ref. EMEA/389995/2009
PRESS RELEASE
Supply shortages of Cerezyme and Fabrazyme - priority access for patients
most in need of treatment recommended
The European Medicines Agency’s (EMEA) Committee for Medicinal Products for Human Use
(CHMP) has recommended that patients who are in greatest need of treatment are given priority access
to Cerezyme (imiglucerase) and Fabrazyme (agalsidase beta) during the expected supply shortage of
these two medicines over the next few months.
Cerezyme and Fabrazyme are both used to treat rare, inherited enzyme-deficiency disorders.
Cerezyme is used in patients with Gaucher disease, a disease in which patients do not have enough of
an enzyme called alglucerase. Fabrazyme is used in patients with Fabry disease, a disease in which
patients do not have enough of an enzyme called alpha-galactosidase A.
The supply shortage is caused by the shutting down of Genzyme’s production site in Allston Landing,
in the United States of America, where both medicines are produced. The company found a viral
contamination (calicivirus of the type Vesivirus 2117) and has shut down the production facility for a
sanitization of the bioreactors. The virus is not known to cause disease in humans, but it may affect the
quantity, but not the quality, of the enzymes produced in the bioreactors. An in-depth investigation of
the cause of the contamination is ongoing.
While the facility is shut down, no new stocks of Cerezyme and Fabrazyme can be produced. All
batches manufactured prior to the detection of the contamination were tested and the Agency
confirmed that they are suitable for release. To ensure that existing stocks last as long as possible until
new batches can be produced, the European Medicines Agency has agreed to some temporary changes
to the way these medicines are prescribed proposed by the company. These changes should be
implemented immediately.
For Cerezyme, priority is given to infants, children and adolescents, and adults with active
disease progression. These patients can continue to receive Cerezyme at the standard dosage
schedule of one infusion every two weeks. However, adult patients without clinical evidence of
active disease progression should receive Cerezyme at a reduced dose (half a dose once every
two weeks) or at a reduced infusion frequency (once a month at their current dose).
For Fabrazyme, priority is given to children and adolescents, and adult male patients, who
should continue to receive Fabrazyme as one infusion every two weeks. However, adult female
patients, in whom the disease is less severe, may receive Fabrazyme at a reduced dose.
These are temporary recommendations and do not change the currently approved Product Information
for either Cerezyme or Fabrazyme. It is expected that these changes will need to continue until the end
of the year.
Notes:
1. More information is available in a question-and-answer document.
2. More information on Cerezyme, including the currently approved Product Information, is
available in the European Public Assessment Report:
http://www.emea.europa.eu/humandocs/Humans/EPAR/cerezyme/cerezyme.htm.
More information on Fabrazyme, including the currently approved Product Information, is
available in the European Public Assessment Report:
http://www.emea.europa.eu/humandocs/Humans/EPAR/fabrazyme/fabrazyme.htm
3. This press release, together with other information on the work of the EMEA, can be found on
the EMEA website: www.emea.europa.eu
Media enquiries only to:
Martin Harvey Allchurch or Monika Benstetter
Tel. (44-20) 74 18 84 27, E-mail press@emea.europa.eu
7 Westferry Circus, Canary Wharf, London, E14 4HB, UK
Tel. (44-20) 74 18 84 00 Fax (44-20) 74 18 84 09
E-mail: mail@emea.europa.eu http://www.emea.europa.eu
25 juin 2009
Comment la situation a été gérée (Vesivirus 2117)
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How is the supply situation managed?
We recognize that access to treatment is a top concern for physicians, other health care providers, patients and their families during this temporary period of Cerezyme (Imiglucerase) and Fabrazyme (Agalsidase beta) supply constraints. It is our top priority as well. During this time period, we are committed to approaching access in a thoughtful, fair, and transparent manner according to these guiding principles for the allocation of the existing supply of Cerezyme and Fabrazyme:
Genzyme will work within the framework set by the regulatory authorities, to facilitate a consultation with expert clinicians and patient group leaders in order to implement the recommendations with the goal of preserving enough supply for the most vulnerable patients. To do this, the recommendations will ask a larger group of patients to conserve supply by missing or reducing doses for a temporary period, beginning as soon as possible.
The decision to conserve supply in this way ultimately lies with each individual patient and their physician. Genzyme cannot determine this treatment allocation on an individual basis.
Genzyme plans to manage the supply constraint during this period on a global basis – with all countries and regions contributing fairly, and without reference to commercial or charitable status.
We believe that working together as a community will help allow us to manage through this period of tight supply in the best way possible.
This web site contains forward-looking statements regarding Genzyme’s business, including without limitation: its assessment of the impact of the Vesivirus on the company, including the duration of the production interruption at its Allston facility, the expected timing and duration of the Cerezyme and Fabrazyme supply constraint, and Genzyme’s plans regarding management of the supply constraint and its ability to preserve product for the most vulnerable patients. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: that Genzyme is unable to resume production of Fabrazyme and Cerezyme by the end of July due to its failure to sanitize the facility, concerns from regulatory authorities regarding production at the facility, or any other reason; that lots of inventory cannot be released because they test positive for the virus or any other reason; that the duration of the supply constraint is longer than anticipated; whether the needed number of patients and their physicians cooperate with the recommendations made in order to conserve supply and how quickly people begin conserving product; the receipt of regulatory consents, if and to the extent required, for the recommendations made to conserve supply; the accuracy of Genzyme’s product demand estimates; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Form 10-Q for the quarter ended March 31, 2009. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this site. These statements speak only as of the date and time set forth on the site posting in which the statements are made.
06/23/2009 at 02:38 PM | Permalink
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Informations sur l'approbation de la Cerezyme (Vesivirus 2117)
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06/19/2009
Information about FDA approval of some inventory of Cerezyme® (imiglucerase for injection) on Wednesday, June 17, 2009
We would like to share more information with you about the recent decision by the FDA to allow us to resume shipments of Cerezyme® (imiglucerase for injection) from our Allston facility.
On Tuesday, June 16, Genzyme explained in a conference call with the business community that some batches of Cerezyme at the Allston facility were being tested for the presence of Vesivirus 2117, using a technique called polymerase chain reaction (or PCR). No evidence of the virus was detected. We provided this information to the FDA on the morning of Wednesday, June 17. Based on their review of this information, the FDA subsequently authorized Genzyme to begin shipping these tested lots of Cerezyme in inventory that have completed testing. We continue to work with the FDA to test additional lots of Cerezyme inventory that have not yet been released.
However, even with the release of this inventory as a result of the authorization from the FDA, Genzyme still anticipates a supply constraint for Cerezyme starting during the August timeframe. We will carefully manage inventories of Cerezyme in conjunction with regulatory authorities, patient groups, physicians, and other health care providers, with the goal of protecting the most vulnerable patients.
This web site contains forward-looking statements regarding Genzyme’s business, including without limitation: its assessment of the impact of the Vesivirus on the company, including the duration of the production interruption at its Allston facility, and the expected timing and duration of the Cerezyme and Fabrazyme supply constraint. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: that Genzyme is unable to resume production of Fabrazyme and Cerezyme by the end of July due to its failure to sanitize the facility, concerns from regulatory authorities regarding production at the facility, or any other reason; that lots of inventory being tested cannot be released because they test positive for the virus or any other reason; that the duration of the supply constraint is longer than anticipated; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Form 10-Q for the quarter ended March 31, 2009. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this site. These statements speak only as of the date and time set forth on the site posting in which the statements are made.
06/19/2009 at 04:18 PM | Permalink
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Information sur la situation de Genzyme(Vesivirus 2117)
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Supply Update Facts
In response to your questions, we'd like to share the following information about Genzyme's supply situation. We will continue to share more information over time. Please refer back to this site or subscribe by email to receive future updates.
Genzyme has identified a virus in a single bioreactor used to manufacture Cerezyme at its Allston facility. This virus, Vesivirus 2117, is not known to cause disease in humans, but it impairs the viability of CHO cells.
We have tested some of the finished vials from affected lots of Cerezyme and the test was negative for Vesivirus 2117. The FDA has authorized us to begin shipping these tested lots of Cerezyme in inventory. We continue to work with the FDA to test additional lots of Cerezyme inventory that have not yet been released, and will provide more information as it becomes available.
Shipments of Fabrazyme are not on hold. This virus has not been detected in the production process for Fabrazyme.
Genzyme has temporarily suspended bulk production of Cerezyme and Fabrazyme in order to sanitize the Allston facility. We expect to restore full operations there in the latter half of July.
Current Cerezyme and Fabrazyme inventories are not sufficient to avoid shortages during this period of suspended production and recovery.
Genzyme continues to evaluate the impact of the interruption in production on the timing and magnitude of constraints on Cerezyme and Fabrazyme supply. The company currently expects the period of constraint for each product to last approximately 6-8 weeks. This period is expected to begin in August for Cerezyme and October for Fabrazyme.
We will carefully manage Cerezyme and Fabrazyme inventories in conjunction with regulatory authorities, patient groups, physicians, and other health care providers, with the goal of protecting the most vulnerable patients.
We believe that inventories will stabilize by the end of 2009.
Myozyme and Aldurazyme are not affected by the current situation.
This web site contains forward-looking statements regarding Genzyme’s business, including without limitation: its assessment of the impact of the Vesivirus on the company, including the duration of the production interruption at its Allston facility, and the expected timing and duration of the Cerezyme and Fabrazyme supply constraint. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: that Genzyme is unable to resume production of Fabrazyme and Cerezyme by the end of July due to its failure to sanitize the facility, concerns from regulatory authorities regarding production at the facility, or any other reason; that lots of inventory being tested cannot be released because they test positive for the virus or any other reason; that the duration of the supply constraint is longer than anticipated; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Form 10-Q for the quarter ended March 31, 2009. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this site. These statements speak only as of the date and time set forth on the site posting in which the statements are made.
06/19/2009 at 08:57 AM | Permalink
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23 juin 2009
FDA : (Vesivirus 2117) d'avertissement à Genzyme du 27/02/2009
Genzyme Corporation 02/27/2009
Department of Health and Human Services
Public Health Service
Food and Drug Administration
New England District
One Montvale Avenue
Stoneham, Massachusetts 02180
(781) 596-7700
FAX: (781) 596-7896
WARNING LETTER
NWE-08-09W
VIA FACSIMILE & CERTIFIED MAIL
February 27, 2009
Mr. Henri Termeer
Chairman, President and CEO
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
Mr. Termeer:
The Food and Drug Administration (FDA) conducted an inspection of Genzyme Allston Landing Facility, located at 500 Soldiers Field Road in Allston, MA, from September 15 – October 10, 2008. During the inspection the FDA investigators documented significant deviations from current good manufacturing practice (CGMP) in the manufacture of licensed therapeutic drug products, bulk drug substances, and drug components. These products include Fabrazyme®, Cerezyme®, and Myozyme®. These deviations from CGMP include non-compliance with section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (FD&C Act), the requirements of your biologics license application approved under 351 of the Public Health Service Act (PHS Act), and Title 21, Code of Federal Regulations (21 CFR) Parts 210 and 211.
At the close of the inspection the investigators issued a form FDA 483, Inspectional Observations, which describe a number of significant objectionable conditions relating to your firm’s compliance with CGMP. Significant deviations observed during the inspection include, but are not limited to, the following:
CGMP DEFICIENCIES CONCERNING DRUG PRODUCTS
1. Failure to establish and follow written procedures designed to prevent microbiological contamination of drug products purporting to be sterile [21 CFR § 211.113(b)]. For example:
a. Air flow pattern testing studies, executed in August of 2007 during the operational qualification of the HVAC system for fill suite FF2-16, do not fully demonstrate air flow movement away from work surfaces during representative personnel activities and manual simulations of the aseptic filling processes. For example the following operations and practices were not preformed during air flow pattern testing studies:
1. Critical aseptic connections
2. Routine functions of aseptic core operators, for example:
• Manually placing stoppers or reorienting stoppers using forceps for filled vials
• Withdrawing unfilled vials from the filling line for weight checks
• Redirecting filled vials typically with stoppers on the exit feed wheel
3. Unidirectional air flow over the rotary in-feed table
4. Opening the lyophilizer door or the automated double doors into the aseptic preparation area
5. Active viable air sampling
b. The aseptic filling of drug products on the (b)(4) filling line at the speed of (b)(4) has not been validated.
CGMP DEFICIENCIES CONCERNING BULK DRUG SUBSTANCES AND DRUG COMPONENTS
In addition, the inspection covered active pharmaceutical ingredients and significant deviations in the manufacture of your bulk drug substance and drug components were observed during the inspection. These deviations cause your bulk drug substances and drug components to be adulterated within the meaning of Section 501(a)(2)(B) of the FD&C Act. Specific areas of concern include, but are not limited to, the following:
Production and Process Controls
2. You failed to assure that there are written production and process controls designed to assure that the drug has the identity, strength, quality, and purity they purport or are represented to possess. For example:
a. Your firm does not conduct adequate monitoring of bioburden after hold times of intermediates or pooled buffers during purification of Fabrazyme®, Myozyme®, and Cerezyme®.
b. Pooled buffers used in purification steps are not adequately controlled for composition. Specifically, the current procedural and automated in-process controls for formulating pooled buffers do not assure that the pooled buffers will meet their specifications.
Your follow up to these documented deviations did not include training of operators or those supervising formulation operations.
Maintenance of Equipment
3. Written procedures are not followed for the maintenance of equipment used in the manufacture, processing, packaging or holding of drug substances. For example:
a. Internal surfaces and manual valves on the stainless steel chromatography columns used during drug substance purification are not adequately maintained. Maintenance has never been performed on the interior of columns to prevent adverse impact on cell cultures due to metal contamination. Visible rouging was observed on the exterior of the chromatography skid (b)(4) used in purification of Myozyme®.
b. For the Cryoshippers which are used to transport master cell banks and working cell banks between manufacturing facilities: (1) The use of these cryoshippers has not been validated, (2) Maintenance has not been performed on any of the (b)(4) shippers in use at the time of the inspection, and (3) The manual for these shippers states that the life expectancy of the shippers is 5 years. (b)(4) of these shippers have been in use since approximately late 2002 or early 2003.
Computerized Systems
4. Your firm failed to maintain computerized systems in a validated state. For example, the (b)(4) console, used for formulation for the elution buffer for Fabrazyme®, has not been updated since 1999. The specific gravity value entered into this system in 1999 is incorrect.
The deficiencies described in this letter are indicative of your quality control unit’s failure to fulfill its responsibility to assure the identity, strength, quality, and purity of your drug products and drug substances.
Genzyme’s written responses dated October 31, 2008, and February 23, 2009
We have reviewed your written responses dated October 31, 2008, and February 23, 2009, addressing Form FDA 483 issued October 10, 2008, and acknowledge your report of completed and in-progress corrective and preventive actions. Additional details to fully evaluate the adequacy of the corrective actions are needed. Our evaluation of your responses and request for further information follows, and is numbered to correspond to the items listed on the Form FDA 483:
Observation 1
Please provide the protocol(s) for your engineering studies and procedures for your new bioburden monitoring program. Regarding your procedures for collecting data to establish bioburden action limits for purification intermediates and drug substance, please address
• whether the (b)(4)referenced in your October 31, 2008 response are from different (b)(4) production lots.
• the basis for any sampling performed.
• the basis upon which appropriate action limits will be established, particularly with regard to infrequently manufactured products.
Please provide an update on the bioburden monitoring programs described in your responses.
Also, please explain your procedures for tracking the length of time that intermediates, drug substance, and buffers have been held.
Observation 2
Please provide the protocol(s) or procedure(s) for collecting data to establish bioburden action limits for pooled buffers. Also, please address
• whether the (b)(4) referenced in your October 31, 2008 response are from (b)(4) different production lots.
• the basis for any sampling performed.
• the basis upon which appropriate action limits will be established, particularly with regard to infrequently manufactured products.
Please provide an update on the bioburden monitoring programs described in your responses.
Please provide an update on the initial evaluation of buffer composition and provide the protocol(s) for the follow up studies referred to in your February 23, 2009 response.
Please provide a summary of the “technical evaluation of the in-process controls tests used to confirm buffer formulation” to which you committed to conduct in your October 31, 2008 written response.
Please address re-training of the operators formulating buffers and those supervising these operations. Our inspection noted that your firm documented deviations in the formulation of pooled buffers, but failed to conduct re-training as follow-up to the deviations to prevent their recurrence.
Observation 6
Your February 23, 2009 response indicates that you have completed your proposed corrective actions with respect to Observation 6, which included an additional air flow pattern study to qualify the HVAC system for fill suite FF2-16. Please indicate if your firm continued aseptic filling operations in fill suite FF2-16 prior to completing this air flow pattern study. If you continued filling operations please provide your justification and evaluation of product impact. In addition, please provide the final report from the air flow pattern study.
Observation 4B, 7, & 11
Your October 31, 2008 response indicates your firm continues to operate the (b)(4) aseptic fill line at speeds up to (b)(4) prior to validating the operation. Please provide your justification and evaluation of product impact.
Please clarify when your firm intends to validate the aseptic filling line. In response to FDA 483 Observation 7, you committed to execute validation of the fill line speed in December 2008. However, in response to FDA 483 Observation 11, you committed to validating the fill line speed in the third quarter of 2009. It is not clear when you will validate the aseptic fill line. Please provide specific details and documentation of your proposed action.
Observation 9
Please indicate if the chromatography column in question remains in use, if it has been evaluated or if maintenance has been performed. If the column is or will remain in use, please provide your justification, including evaluation of the column and any maintenance performed, and an evaluation of product impact.
Observation 10
We acknowledge your commitment not to use the cryoshippers prior to execution of validation for transport of cell banks between the Framingham, MA and Allston, MA facilities. However, these cryoshippers are also used to transfer cell banks from Framingham, MA to San Diego, CA and to Belgium. Please indicate whether you have also ceased using the cryoshippers for cell bank shipments to San Diego, CA, and Belgium until the validation is completed. If not, please provide a justification.
Observation 15
We acknowledge your commitment to identify inconsistencies between the (b)(4) automated system and the production records regarding specific gravity values for buffers your firm manufactures (e.g. Fabrazyme Elution Buffer).
The inspection team noted that this automated system, containing formulas and recipes for buffers was programmed in 1999 and has not been reviewed or updated. We are concerned that other discrepancies in other values may exist. Please comment on how you will assure all values programmed (b)(4) into the automated system, and other automated systems, are consistent with current master batch records.
Neither this letter nor the observations noted on the Form FDA 483, which were discussed with you at the conclusion of the inspection, are intended to be an all-inclusive list of deficiencies that may exist at your facility. It is your responsibility as management to assure that your establishment is in compliance with the provisions of the FD&C Act, PHS Act, all applicable federal laws and regulations, and the standards in your license. Federal agencies are advised of the issuance of all Warning Letters about biological products so that they may take this information into account when considering the award of contracts.
Please notify this office in writing, within 15 working days of the receipt of this letter, of any steps you have taken or will take to correct the noted violations and to prevent their recurrence .Include any documentation necessary to show that correction has been achieved. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed. Failure to promptly correct these deviations may result in further regulatory action without further notice. Such actions may include license suspension and/or revocation, seizure or injunction.
Additionally, FDA may withhold approval of requests for export certificates, or approval of pending new drug application listing your facility as a manufacturer until the above violations are corrected. A re-inspection may be necessary.
If you no longer manufacture or market any of your drug products, your response should so indicate, including the reasons for, and the date on which, you ceased production.
Please direct your response or any questions you may have to Amber Wardwell, Compliance officer, Food and Drug Administration. One Montvale Avenue 4th Floor, Stoneham, Massachusetts 02180. Her telephone is (781) 596-596-7823.
Sincerely yours,
/S/
John R. Marzilli
District Director
New England District
21 juin 2009
Keeping you informed
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
For over 25 years, Genzyme has been committed to serving unmet medical needs around the world, with special emphasis on very rare, genetic diseases.
As indicated in our June 16th press release, we have temporarily suspended bulk production at our Allston Landing facility to sanitize the plant because we discovered a virus that impairs cell growth. The virus strain, Vesivirus 2117, has not been shown to cause human infection. We have a plan in place to resolve this issue quickly and expect to return the plant to full operation by the end of July.
Given our current product inventories, we expect periods of constrained supply to occur in August for Cerezyme® (imiglucerase for injection) and starting in September for Fabrazyme® (agalsidase beta). Our priority is to minimize the disruption for patients who rely on these products. Many people across Genzyme are working in a focused way to address this issue, and we have already made great progress in identifying the problem, establishing a plan of action, and getting on with the work.
We take this matter very seriously, and are working closely with regulatory officials, physicians and other heathcare providers, and patient communities worldwide.
In the spirit of transparency and collaboration – values that have guided our company from day 1 - this site has been developed as a way for us to share with you the progress we are making to restore our bulk production to full capacity. We hope that this website will be helpful and encourage you to check back frequently for new information.
Please see below for a message from Geoff McDonough, Genzyme Senior Vice President:
We also want to hear from you. If you have questions or feedback of any kind, please contact us.
This web site contains forward-looking statements regarding Genzyme’s business, including without limitation: its assessment of the impact of the Vesivirus on the company, including the duration of the production interruption at its Allston facility, and the expected timing and duration of the Cerezyme and Fabrazyme supply constraint. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: that Genzyme is unable to resume production of Fabrazyme and Cerezyme by the end of July due to its failure to sanitize the facility, concerns from regulatory authorities regarding production at the facility, or any other reason; that lots of inventory being tested cannot be released because they test positive for the virus or any other reason; that the duration of the supply constraint is longer than anticipated; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Form 10-Q for the quarter ended March 31, 2009. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this site. These statements speak only as of the date and time set forth on the site posting in which the statements are made.
http://genzymesupplyupdate.typepad.com/
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Genzyme Temporarily Interrupts Production at Allston Plant
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
Date: June 16, 2009
Genzyme Corporation (NASDAQ: GENZ) today announced that it has detected a virus that impairs cell growth in one of six bioreactors at its Allston Landing manufacturing facility. The company has decided to temporarily interrupt bulk production at the plant to sanitize the facility. Genzyme is collaborating with regulatory agencies as it works to resume production. The company expects the plant to be fully operational by the end of July.
The virus strain, Vesivirus 2117, has not been shown to cause human infection. It is known to interfere with the growth of CHO cells used to produce biologic drugs and was likely introduced through a nutrient used in the manufacturing process. Genzyme has now confirmed that this virus was the cause of declines in cell productivity at its Allston and Geel facilities in two previous instances in 2008, which were subsequently fully addressed. The company was able to detect the virus in this case using a highly specific assay it developed after standard tests were unable to identify the cause of the previous productivity declines. Genzyme is adding steps to increase the robustness of its raw materials screening and viral removal processes.
Current inventories for Cerezyme® (imiglucerase for injection) and Fabrazyme® (agalsidase beta) are not sufficient to meet projected global demand. The timing and extent of the Cerezyme supply constraint is being clarified and will be communicated as soon as possible. The company expects Fabrazyme supply constraints to occur for a limited period beginning in September. The company will work with physicians, patients and regulators to minimize the impact of this constraint.
“The patients who need these therapies are our priority,” said Henri A. Termeer, Genzyme’s chairman and chief executive officer. “We are confident in the quality of the products produced in Allston and in our ability to resolve the issue affecting the plant. The impact will be temporary.”
Genzyme identified the virus at the Allston plant over the weekend. On Monday morning, the company submitted information to the FDA and EMEA on its findings. The company held a conference call with the FDA on Monday afternoon. With regulatory input, Genzyme is finalizing its action plan and assessing the business impact of this situation. The company will provide updated financial guidance as soon as possible.
Conference Call Information
Genzyme will host a conference call today at 12:00 p.m. Eastern. To participate in the call, please dial 773-799-3828 and refer to pass code “Genzyme.” A replay of this call will be available by dialing 402-220-2056 until June 23. This call will also be Webcast live on the investor events section of www.genzyme.com.
About Genzyme
One of the world's leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 11,000 employees in locations spanning the globe and 2008 revenues of $4.6 billion.
With many established products and services helping patients in approximately 100 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company's products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune disease, and diagnostic testing. Genzyme's commitment to innovation continues today with a substantial development program focused on these fields, as well as cardiovascular disease, neurodegenerative diseases, and other areas of unmet medical need.
This press release contains forward-looking statements regarding Genzyme’s business, including without limitation: its assessment of the impact of the Vesivirus on the company, including the duration of the production interruption at its Allston Landing manufacturing facility and the expected duration of the Fabrazyme supply constraint. These statements are subject to risks and uncertainties that could cause actual results to differ materially from those forecasted. These risks and uncertainties include, among others: that Genzyme is unable to resume production of Fabrazyme and Cerezyme by the end of July due to its failure to sanitize the facility, concerns from regulatory authorities regarding production at the facility, or any other reason; that the current inventory in process at the facility cannot be released; and the risks and uncertainties described in Genzyme's SEC reports filed under the Securities Exchange Act of 1934, including the factors discussed under the caption "Risk Factors" in Genzyme's Quarterly Report on Form 10-Q for the quarter ended March 31, 2009. Genzyme cautions investors not to place substantial reliance on the forward-looking statements contained in this press release. These statements speak only as of today’s date and Genzyme undertakes no obligation to update or revise the statements.
Genzyme®, Cerezyme® and Fabrazyme® are registered trademarks of Genzyme Corporation or its subsidiaries. All rights reserved.
Genzyme’s press releases and other company information are available at www.genzyme.com and by calling Genzyme’s investor information line at 1-800-905-4369 within the United States or 1-678-999-4572 outside the United States.
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Genzyme shut down a Massachusetts factory after a virus infected hamster ovary cells used to produce Fabrazyme and Cerezyme
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
Over the weekend, drugmaker Genzyme shut down a Massachusetts factory after a virus infected hamster ovary cells used to produce Fabrazyme and Cerezyme, drugs for two rare genetic disorders.
Genzyme is the sole supplier of the medicines in the United States. When stocks of the medicines run low in August, patients may have to ration supplies for four to six weeks. Jack Johnson, a 46-year-old Missourian, who takes Fabrazyme, says the shutdown “is a concern for patients . . . but we’ll just have to wait and see how this all plays out.”
The U.S. Food and Drug Administration (FDA) has put shipments of Cerezyme and Fabrazyme on hold while the company conducts DNA tests on its current stockpiles, Genzyme Executive Vice President David Meeker said during a conference call yesterday. He expects the plant to reopen by the end of July, and supplies to be steady by the end of the year.
This was the second time the company’s production vats have been infected with a virus called Vesivirus 2117, which first hit its facilities in 2008. In February, the FDA also sent a warning letter to the plant after an inspection uncovered quality problems. However, company representatives said that Genzyme had already addressed the FDA’s concerns in that letter and that they were not linked to the viral infection, which was caused by contamination in a still-unidentified nutrient added to the cell mixture. “Contamination may be transient and we may never identify the source,” Meeker said.
Genzyme's Chief Medical Officer, Richard Moscicki, says the virus was unable to infect human cells during their own laboratory tests. Though the virus is a member of the Calicivirus family known to infect humans, Vesivirus has only “dubious” associations with human disease, says Moscicki. Alvin Smith, a Calicivirus expert formerly with Oregon State University, and colleagues published a paper in 2006 claiming an association between Vesivirus, hepatitis and liver damage. But the team’s results have since been questioned by Dutch researchers who wereunable to replicate them in the Netherlands.
More important to patients is the question of how long the shortages will last. Cerezyme is used to treat Gaucher’s disease, an enzyme deficiency that can cause osteoporosis and an enlarged spleen or liver. Fabrazyme is used to treat Fabry disease, another enzyme deficiency, that causes the build-up of fatty acids and oils in the eyes and kidneys along with cardiovascular and nervous system problems. The diseases affect about 8000 people worldwide. Genzyme’s enzyme replacement therapies cost approximately $200,000 per year.
Rhonda Buyers, CEO of the National Gaucher Foundation, says Genzyme told her group the company is working diligently to keep the plant closure short.
http://www.scientificamerican.com/blog/60-second-science/post.cfm?id=virus-hits-genzyme-plant-halting-pr-2009-06-17
Genzyme Plant Temporarily Closes; 2 Drugs' Supplies To Be Hurt
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Ghislaine SURREL
maladies-lysosomales-subscribe@yahoogroupes.fr
Tuesday June 16th, 2009 / 15h38
DOW JONES NEWSWIRES Genzyme Corp. (GENZ) said a Massachusetts plant will be out of commission for at least a month following the company's discovery of a virus over the weekend, with the drug maker expecting supplies of two drugs to become constrained.
Shares slumped 7.6% in recent premarket action to $51.33.
Investigators earlier this year found "significant objectionable conditions" during an inspection at the Allston Landing plant, outlining a number of deficiencies in the manufacturing process.
The Vesivirus 2117 virus strain, found in a bioreactor, hasn't been shown to cause human infection, but it is known to interfere with the growth of cells used to produce biologic drugs. It was likely introduced through a nutrient used in the manufacturing process, Genzyme said, and has confirmed the virus caused declines in cell productivity in two instances last year.
The drug firm, whose product portfolio focuses on rare genetic disorders as well as organ transplants, cancer and kidney disease, said it is collaborating with regulatory agencies to resume production and expects the plant to return to full operation by the end of July.
While assessing the business impact, Genzyme said current inventories for Gaucher treatment Cerezyme and Fabry's drug Fabrazyme aren't sufficient to meet projected global demand. The company doesn't know when or for how long Cerezyme supplies will be constrained but said Fabrazyme should be affected "for a limited time" starting in September.
-By Mike Barris, Dow Jones Newswires; 201-938-5658; mike.barris@dowjones.com;
Click here to go to Dow Jones NewsPlus, a web front page of today's most important business and market news, analysis and commentary: http://www.djnewsplus.com/access/al?rnd=nMZcyk2ZFp%2BAw7%2BkSZjUjQ%3D%3D. You can use this link on the day this article is published and the following day.
http://www.easybourse.com/bourse-actualite/marches/genzyme-plant-temporarily-closes-2-drugs-supplies-to-684869
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