Genzyme = Corporation, Warning Letter

From: Subject: Genzyme Corporation, Warning Letter Date: Wed, 11 Mar 2009 13:16:09 -0400 MIME-Version: 1.0 Content-Type: multipart/related; type="text/html"; boundary="----=_NextPart_000_0000_01C9A24B.8AF44140" X-MimeOLE: Produced By Microsoft MimeOLE V6.00.2900.5579 This is a multi-part message in MIME format. ------=_NextPart_000_0000_01C9A24B.8AF44140 Content-Type: text/html; charset="iso-8859-1" Content-Transfer-Encoding: quoted-printable Content-Location: http://www.fda.gov/foi/warning_letters/s7123c.htm Genzyme = Corporation, Warning Letter

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Department of Health and Human Services	Public Health Service Food and Drug = Administration
	New England District One Montvale Avenue Stoneham,=20 Massachusetts 02180 (781) 596-7700 FAX: (781) 596-7896=20

WARNING LETTER

NWE-08-09W

VIA FACSIMILE & CERTIFIED MAIL =

February 27, 2009

Mr. Henri Termeer
Chairman, President and CEO
Genzyme = Corporation=20
500 Kendall Street
Cambridge, MA 02142

Mr. Termeer:

The Food and Drug Administration (FDA) conducted an inspection of = Genzyme=20 Allston Landing Facility, located at 500 Soldiers Field Road in Allston, = MA,=20 from September 15 =96 October 10, 2008. During the inspection the FDA=20 investigators documented significant deviations from current good = manufacturing=20 practice (CGMP) in the manufacture of licensed therapeutic drug = products, bulk=20 drug substances, and drug components. These products include = Fabrazyme=AE,=20 Cerezyme=AE, and Myozyme=AE. These deviations from CGMP include = non-compliance with=20 section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act = (FD&C Act),=20 the requirements of your biologics license application approved under = 351 of the=20 Public Health Service Act (PHS Act), and Title 21, Code of Federal = Regulations=20 (21 CFR) Parts 210 and 211.

At the close of the inspection the investigators issued a form FDA = 483,=20 Inspectional Observations, which describe a number of significant = objectionable=20 conditions relating to your firm=92s compliance with CGMP. Significant = deviations=20 observed during the inspection include, but are not limited to, the = following:=20

CGMP DEFICIENCIES CONCERNING DRUG PRODUCTS

1. Failure to establish and follow written procedures designed to = prevent=20 microbiological contamination of drug products purporting to be sterile = [21 CFR=20 =A7 211.113(b)]. For example:

a. Air flow pattern testing studies, executed in August of 2007 = during the=20 operational qualification of the HVAC system for fill suite FF2-16, do = not=20 fully demonstrate air flow movement away from work surfaces during=20 representative personnel activities and manual simulations of the = aseptic=20 filling processes. For example the following operations and practices = were not=20 preformed during air flow pattern testing studies:

1. Critical aseptic connections
2. Routine functions of aseptic = core=20 operators, for example:

=95 Manually placing stoppers or reorienting stoppers using = forceps for=20 filled vials
=95 Withdrawing unfilled vials from the filling = line for=20 weight checks
=95 Redirecting filled vials typically with = stoppers on the=20 exit feed wheel

3. Unidirectional air flow over the rotary in-feed table
4. = Opening the=20 lyophilizer door or the automated double doors into the aseptic = preparation=20 area
5. Active viable air sampling

b. The aseptic filling of drug products on the = (b)(4)=20 filling line at the speed of (b)(4) = has not=20 been validated.

CGMP DEFICIENCIES CONCERNING BULK DRUG SUBSTANCES AND DRUG = COMPONENTS=20

In addition, the inspection covered active pharmaceutical ingredients = and=20 significant deviations in the manufacture of your bulk drug substance = and drug=20 components were observed during the inspection. These deviations cause = your bulk=20 drug substances and drug components to be adulterated within the meaning = of=20 Section 501(a)(2)(B) of the FD&C Act. Specific areas of concern = include, but=20 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,=20 and purity they purport or are represented to possess. For example:

a. Your firm does not conduct adequate monitoring of bioburden = after hold=20 times of intermediates or pooled buffers during purification of = Fabrazyme=AE,=20 Myozyme=AE, and Cerezyme=AE.

b. Pooled buffers used in purification steps are not adequately = controlled=20 for composition. Specifically, the current procedural and automated = in-process=20 controls for formulating pooled buffers do not assure that the pooled = buffers=20 will meet their specifications.

Your follow up to these documented deviations did not include = training of=20 operators or those supervising formulation operations.

Maintenance of Equipment

3. Written procedures are not followed for the maintenance of = equipment used=20 in the manufacture, processing, packaging or holding of drug substances. = For=20 example:

a. Internal surfaces and manual valves on the stainless steel=20 chromatography columns used during drug substance purification are not = adequately maintained. Maintenance has never been performed on the = interior of=20 columns to prevent adverse impact on cell cultures due to metal = contamination.=20 Visible rouging was observed on the exterior of the chromatography = skid=20 (b)(4) used in purification of Myozyme=AE.

b. For the Cryoshippers which are used to transport master cell = banks and=20 working cell banks between manufacturing facilities: (1) The use of = these=20 cryoshippers has not been validated, (2) Maintenance has not been = performed on=20 any of the (b)(4) shippers in use at the time of the=20 inspection, and (3) The manual for these shippers states that the life = expectancy of the shippers is 5 years. (b)(4) of = these=20 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.=20 For example, the (b)(4) console, used for formulation = for the=20 elution buffer for Fabrazyme=AE, has not been updated since 1999. The = specific=20 gravity value entered into this system in 1999 is incorrect.

The deficiencies described in this letter are indicative of your = quality=20 control unit=92s failure to fulfill its responsibility to assure the = identity,=20 strength, quality, and purity of your drug products and drug substances. =

Genzyme=92s written responses dated October 31, 2008, and = February 23,=20 2009

We have reviewed your written responses dated October 31, 2008, and = February=20 23, 2009, addressing Form FDA 483 issued October 10, 2008, and = acknowledge your=20 report of completed and in-progress corrective and preventive actions.=20 Additional details to fully evaluate the adequacy of the corrective = actions are=20 needed. Our evaluation of your responses and request for further = information=20 follows, and is numbered to correspond to the items listed on the Form = FDA 483:=20

Observation 1

Please provide the protocol(s) for your engineering studies and = procedures=20 for your new bioburden monitoring program. Regarding your procedures for = collecting data to establish bioburden action limits for purification=20 intermediates and drug substance, please address

=95 whether the (b)(4)referenced in your October 31, 2008 response = are from=20 different (b)(4) production lots.

=95 the basis for any sampling performed.

=95 the basis upon which appropriate action limits will be = established,=20 particularly with regard to infrequently manufactured products.=20

Please provide an update on the bioburden monitoring programs = described in=20 your responses.

Also, please explain your procedures for tracking the length of time = that=20 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

=95 whether the (b)(4) referenced in your = October 31, 2008=20 response are from (b)(4) different production lots. =

=95 the basis for any sampling performed.

=95 the basis upon which appropriate action limits will be = established,=20 particularly with regard to infrequently manufactured products.=20

Please provide an update on the bioburden monitoring programs = described in=20 your responses.

Please provide an update on the initial evaluation of buffer = composition and=20 provide the protocol(s) for the follow up studies referred to in your = February=20 23, 2009 response.

Please provide a summary of the =93technical evaluation of the = in-process=20 controls tests used to confirm buffer formulation=94 to which you = committed to=20 conduct in your October 31, 2008 written response.

Please address re-training of the operators formulating buffers and = those=20 supervising these operations. Our inspection noted that your firm = documented=20 deviations in the formulation of pooled buffers, but failed to conduct=20 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=20 proposed corrective actions with respect to Observation 6, which = included an=20 additional air flow pattern study to qualify the HVAC system for fill = suite=20 FF2-16. Please indicate if your firm continued aseptic filling = operations in=20 fill suite FF2-16 prior to completing this air flow pattern study. If = you=20 continued filling operations please provide your justification and = evaluation of=20 product impact. In addition, please provide the final report from the = air flow=20 pattern study.

Observation 4B, 7, & 11

Your October 31, 2008 response indicates your firm continues to = operate the=20 (b)(4) aseptic fill line at speeds up to (b)(4) = prior to validating the operation. Please provide your = justification=20 and evaluation of product impact.

Please clarify when your firm intends to validate the aseptic filling = line.=20 In response to FDA 483 Observation 7, you committed to execute = validation of the=20 fill line speed in December 2008. However, in response to FDA 483 = Observation=20 11, you committed to validating the fill line speed in the third quarter = of=20 2009. It is not clear when you will validate the aseptic fill line. = Please=20 provide specific details and documentation of your proposed action.

Observation 9

Please indicate if the chromatography column in question remains in = use, if=20 it has been evaluated or if maintenance has been performed. If the = column is or=20 will remain in use, please provide your justification, including = evaluation of=20 the column and any maintenance performed, and an evaluation of product = impact.=20

Observation 10

We acknowledge your commitment not to use the cryoshippers prior to = execution=20 of validation for transport of cell banks between the Framingham, MA and = Allston, MA facilities. However, these cryoshippers are also used to = transfer=20 cell banks from Framingham, MA to San Diego, CA and to Belgium. Please = indicate=20 whether you have also ceased using the cryoshippers for cell bank = shipments to=20 San Diego, CA, and Belgium until the validation is completed. If not, = please=20 provide a justification.

Observation 15

We acknowledge your commitment to identify inconsistencies between = the=20 (b)(4) automated system and the production records = regarding=20 specific gravity values for buffers your firm manufactures (e.g. = Fabrazyme=20 Elution Buffer).

The inspection team noted that this automated system, containing = formulas and=20 recipes for buffers was programmed in 1999 and has not been reviewed or = updated.=20 We are concerned that other discrepancies in other values may exist. = Please=20 comment on how you will assure all values programmed = (b)(4)=20 into the automated system, and other automated systems, are consistent = with=20 current master batch records.

Neither this letter nor the observations noted on the Form FDA 483, = which=20 were discussed with you at the conclusion of the inspection, are = intended to be=20 an all-inclusive list of deficiencies that may exist at your facility. = It is=20 your responsibility as management to assure that your establishment is = in=20 compliance with the provisions of the FD&C Act, PHS Act, all = applicable=20 federal laws and regulations, and the standards in your license. Federal = agencies are advised of the issuance of all Warning Letters about = biological=20 products so that they may take this information into account when = considering=20 the award of contracts.

Please notify this office in writing, within 15 working days of the = receipt=20 of this letter, of any steps you have taken or will take to correct the = noted=20 violations and to prevent their recurrence .Include any documentation = necessary=20 to show that correction has been achieved. If corrective actions cannot = be=20 completed within 15 working days, state the reason for the delay and the = time=20 within which the corrections will be completed. Failure to promptly = correct=20 these deviations may result in further regulatory action without further = notice.=20 Such actions may include license suspension and/or revocation, seizure = or=20 injunction.

Additionally, FDA may withhold approval of requests = for=20 export certificates, or approval of pending new drug application listing = your=20 facility as a manufacturer until the above violations are corrected. A=20 re-inspection may be necessary.

If you no longer manufacture or = market=20 any of your drug products, your response should so indicate, including = the=20 reasons for, and the date on which, you ceased production.

Please = direct=20 your response or any questions you may have to Amber Wardwell, = Compliance=20 officer, Food and Drug Administration. One Montvale Avenue 4th Floor, = Stoneham,=20 Massachusetts 02180. Her telephone is (781) = 596-596-7823.

Sincerely=20 yours,

/S/

John R. Marzilli
District Director
New England = District

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FDA/Freedom=20 of Information

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