`
`

`

`
`
`)n#21-038
`
`-HFD-17O
`
`- ”210;?”
`
`m
`“21033
`”ll”l'llllllll
`Iliummmmummlmumum
`DRUG NAME: Precedex (dexmedetomidine hc1 I'njcuuuu,
`'
`be?“ ,
`Mas/9
`
`APPLICANT: ABBOTT LABORATORIES
`
`CHEMICAL & THERAPEUTIC CLASSJS
`
`Review Cycle: 1
`Submission Date:12-18-98
`Receipt Date:lZ-18-98
`Goal Date:12-18-99
`ActionzAP
`
`Review Cycle: 3
`Submission Date:
`Receipt Date:
`Goal Date:
`Action:
`
`Action:
`
`Review Cycle: 2
`Submission Date:
`Receipt Date:
`Goal Date:
`Action:
`
`Review Cycle: 4'
`Submission Date:
`Receipt Date:
`Goal Date:
`
`Phone # & Office Room #:301-827-7410, 93-45
`
`I
`
`MEDICALzPatricia Hartwell, M.D., M.B.A.
`
`CH EMISTRY:Michael Theodorakis, Ph.D.
`
`PHARMfl‘OX:Harry Geyer, Ph.D.
`
`BlOMETRlCS: Z.Jonathan Ma, Ph.D.
`
` PROJECT MANAGER/ CSO :Susmita Samanta
`
`
`
`
`
`
`
`
`
`BlOPHARMACEUTlCS:Suresh Doddapaneni, Ph.D.
`
`
`
`
`ABUSE LIABILITY: BeLinda A. Hayes, Ph.D.
`
` MICROBIOLOGIST: Patricia Hughes, Ph.D.
`
`Volume 3 Of 4
`
`Administrative volume #(s): 1
`Clinical volume #(s): 2
`CMC volume #(s): 3
`
`5-
`
`Phannacology/Toxicology volume #(s): 4
`
`

`

`ODE II ACTION PACKAGE TABLE OF CONTENTS
`
`Application #2’1-038'
`
`Drug Name: Precedex (dexmedetomidine Hydrochloride injection), 2 mL ampule/2 mL vial, 100
`
`mcg/mL
`
`Applicant: Abbott Laboratories
`
`Chem/Ther. Type: 1 S
`
`CSO/PM: Susmita Samanta
`
`Phone? 301-827-7410
`
`*HFD-17O
`
`Original Application Date: December 18, 1998 Original Receipt Date: December 18, 1998
`
`
`i
`
`‘
`
`CURRENT USER FEE GOAL DATE: December 18, l999DateTableofContentsCompleted2-9/13/99
`.
`-
`,,
`_
`.
`X(complered),
`Section A:
`i a' e"
`N/A (not applicable),
`or Comment
`
`
`Tab A-l
`
`Action.Letter(s)
`
`Current ActionzAP
`
`' Tab A-2
`
`Phase 4 Commitments:
`
`a. Copy of applicants communication committing to Phase 4
`
`b. Agency Correspondence requesting Phase 4 Commitments
`
`Tab A-3
`
`FDA revised Labels & Labeling and Reviews:
`(Separate each version/cycle with a colored sheet)
`
`a. Package Insert
`
`Tab A-4
`
`Original Proposed Labeling
`
`Tab A-S
`
`Foreign Labeling:
`
`...............................................................
`
`a. Foreign Marketing History
`
`Tab A-6
`Tab A-7
`Tab A-8
`
`b. Foreign Labeling and Review(s)
`"
`Labeling and Nomenclature Committee’s Tradename Review
`Summary Memoranda (e.g., Division Director, Group Leader, Office)
`Copy of Patent Statement
`
`‘
`
`Exclusivity Checklist (and any requests for exclusivity)
`
`Debannent Statements ......................................................................
`
`Tab A-9
`
`Correspondences, Faxes, & Telecons
`
`Tab A-lO Minutes of Meetings:
`
`3. ,End-of-Phase 11 meeting
`
`b. Pre-NDA meeting(s)
`
`c. Filing meeting
`
`d. Other meetings
`
`Tab A-l ]
`
`Advisory Committee Meeting:
`
`a. Questions Considered by the committee
`b. List of Attendees
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`ODE II ACTION PACKAGE TABLE OF CONTENTS (continued)
`
`_App1ication’#21-038 Drug Name: Dexmedetomidine HCL
`
`gamma;
`
`'
`
`Climallnhunafism
`
`"
`
`,_.
`
`X (completed),
`N/A (not applicab|e),
`or Comment
`
`Tab B-l
`
`Tab B-2
`
`Tab B-3
`Tab B-4
`
`Tab-B-S
`Tab B-6
`Tab B-7
`
`Tab 8-8
`' Tab B-9
`
`Clinical Reviews and Memoranda .......................................................
`
`Safety Update Reviews .....................................................................
`
`'......................
`Pediatric Page
`Statistical (Clinical) Review and Memoranda ..........................................
`
`summary of Safety (from the summary volume of the application) .....................
`
`- Biopharmaceutics Review and Memoranda ............................................
`Abuse Liability Review......................................
`DSI Audits ....................................................................................
`
`Summary of Efficacy (fiom the summary volume of the application) ..................
`
`Section E;
`
`-
`
`1
`
`a
`
`.
`
`a
`
`‘
`g'
`W
`
`'
`
`[is “M 1
`
`X(completed),
`N/A (not applicable),
`or Comment
`
`Tab C-l .
`
`CMC Reviews and Memoranda ..........................‘. ..............................
`
`Tab 02
`
`DMF Reviews ..............................................................................
`
`Tab 03
`
`EA Reviews/FONSI .......................................................................
`
`Tab C-4
`
`Micro Review (validation of sterilization) .............................................
`
`Tab C-5
`
`Statistical Review of drug stability
`
`N..................................
`
`‘
`
`Tab C-6
`
`Inspection of facilities => Decision:
`
`-
`
`Date:
`
`Tab 07
`
`Methods Validation Information ........................................................
`
`
`
`
`
`Section D;
`
`
`
`X (completed),
`N/A (not applicable),
`or Comment ..
`
`Tab D-l
`
`Pharmacologyfl'oxicology Reviews and Memoranda ...............................
`
`Tab 112
`
`Carcinogenicity Review (statistical)
`
`......................
`
`_
`
`CAC/Executive Committee Report .....................................................
`Tab D-3
`
`ADDITIONAL NOTES:
`
`—-—-——————————————__.___________—__
`
`

`

`‘ aABBDTT -
`
`-
`
`Hoseital Products Division
`Abbott Laboratories
`oaas. Bldg. A930
`200 Abbott Park Road
`Abbott Park. Illinois 60064-6157
`
`'
`
`
`
`REQUEST FOR A CATEGOEICAL EXCLUSlON
`
`
`
`
`Abbott Laboratories hereby requests
`a CATEGORICAL EXCLUSION
`requirements of an Environmental Impact Report under the provisions of 21 CFR
`
`
`
`
`ABBOTT LABORATORIES
`
`
`
`
`
`2%,Wm 32/
`
`e
`
`Thomas F. Willer, PhD.
`Associate Director, Regulatory Affairs
`Hospital Products Division
`Phone: (847) 937-6845
`Fax:
`(847) 938—7867
`lnternet: WILLETF@hpd.abbott.com
`
`-
`
`-
`
`

`

`CERTIFICATIoN-QOF COMPLIANCE
`Rocky Mount, North Carolina Facility
`
`Abbott Laboratoriee certiflee that it in in complionce with. or on an enforceable schedule to be in
`compliance with.oll emittsion requirements .set forth in permits. consent decrees; and
`administrative orders applicable to solution preparation and filling of Dexmedetomidine
`E
`Hydrochloride inlectlon at its facility in Rocky Mount. North Carolina as well aoemlesion
`requirements set forth in applicable federal. state, and local environmental and occupational
`exposure statutes and regulations applicable to solution preparation and filling of
`Dexmedetomidlno Hydrochloride Injection at its facility in Rocky Mount. North Carolina.
`
`-
`
`
`Signature: gag. .
`
`John Robbins
`Principal Environmental Specialist
`Abbott Labomtol'leS.
`Hospital Products Division‘ '
`
`Date: W7
`
`‘ APPEARS THlS WAY
`on ORlGlNAl.
`
`mytpuvx
`
`‘
`
`‘
`
`as, an inn
`ASBA-BQEMVB) SHIUJJU 533 6880 wavzet
`sr/S'd
`W
`
`

`

`
`
`gnu.
`
`,‘f/ DEPARTMENT OF HEALTH & HUMAN SERVICES
`i. C
`Memorandum
`
`Public Health Service
`
`FoodandDrugAdniristratim
`
`DATE:
`
`November 29, 1999
`
`FROM: Albinus M. I_)'Sa, Ph.D.
`
`.TO:
`
`Cynthia McCormick, M.D.
`
`\C3\
`
`-
`
`1'1
`
`SUBJECT: .
`
`NDA 21-038, CMC review status
`
`‘
`
`I am writing this memo to inform you that currently all CMC issues are resolved and ”that the NDA
`from the CMC stand point is recommended for approval.
`
`~
`
`.
`
`‘ Previously, our recommendation in the CMC review #1, dated milk; 30, 1999, was agprovable. This
`was because the Office of Compliance recommendation was pending and the BE indicated that
`,. M"
`Upon talking with the compliance officer, Mr. Richard Friedman and the inspector Mr. Thomas
`Arista, I was informed thatW "X _
`.The
`applicantwas working on the deficiencies listed in the form—483, as listed by the inspector. All of
`these issues pertained to Current Good Manufacturing Practice. However, the inspection deficiencies
`only applied to drug substances that were to be used in manufacturing a drug product via an
`aseptically filled sterile process. Dexmetatomidine HCl, is a terminally sterilized product and
`therefore the issues in the form-483, did not apply to this particular NDA. The drug product
`manufacturing facility was found to be acceptable from the CGMP perspective. The office of
`compliance could not however provide an acceptable recommendation to the £138 request because
`of the pending CGMP issues at the firm.
`
`A consult was initiated (based on an E-mail from Dr. Rappaport) to Microbiology to seek advice on . {/9
`the micro issues that compliance had raised in the form—483; the response is pending. However, in J 7,:
`the interim, the firm has complied with all of the CGMP observations, and the Office of Compliance ‘..J 15"
`on November 19, 1999, reported an acceptable. status for all the facilities in the‘EES request.
`'-
`Therefore from the CMC standpoint, this application is recommended for approval.
`’7 ~.1
`,
`.
`\
`J) /
`J‘-
`The other issues that needed clarification were as follows, however none ofthese are approvability
`3/
`issues:
`3,
`
`r
`'
`
`ExCept for one, all issues raised in the NDA review pertain to labeling. On the one issue, the
`applicant has tightened the specs for endotoxin. The reviewer was asking for data to support the new
`specs. At this point this data may not be important because the marketed product will have to meet
`these new tighter specs.
`The applicant has satisfactorily addressed the issues raised in DMF. The stability protocol for the
`drug substance is modified as requested, and a plicant has agreed to perform acceptance testing of
`every lot of drug substance based on the speci ications of the drug substance. The DMF holder will
`have an expiration date for the drug substance of 3 years, based on the stability data for the drug .
`substance.
`
`And finally, a standard statement should on methods validation should be included in the approval
`letter, because the FDA labs have not yet completed the validation.
`-
`
`

`

`
`
`FOOD and DRUG ADMINISTRATION
`CENTER of DRUG EVALUATION and RESEARCH
`
`DIVISION OF ANESTHETICS, CRITICAL CARE and ADDICTION DRUG
`PRODUCTS ( DACCADP)
`HFD- 17 o
`
`NDA:21-038
`
`CHEMISTRY REVIEW #:1
`
`- = REVIEW DATE: 30-JUN-99
`
`‘
`
`_
`
`SUBMISSION TYPE
`ORIGINAL
`—
`AMENDMENTIAC]
`AMENDMENT[BC]
`
`DOCUMENT DATE
`l8-DEC-98
`- 09aFEB-99
`30-APR-99
`
`CDER DATE ASSIGNED DATE
`Is-DEc-98
`23-DEC-98
`
`O3-MAY-99
`
`__
`
`NAME & ADDRESS OF APPLICANT:
`Abbott Laboratories‘
`Hospital Products Division
`D-389, Bldg. AP30200
`Abbott Park Road
`
`Abbott Park, Illinois 60064-3537
`
`_Attn: Thomas F. WillerjPhD.
`Assistant Director. Regulatory Affairs
`tel.: 874-937-6845
`
`DRUG PRODUCT NAME
`
`Progrietarv:
`Nongrogrietarv/USAN:
`Code Name/#:
`
`~\——
`dexmedetornidine HCl
`
`Chem.Tvge/Ther.Class:
`
`1 S
`
`PHARMACOL.CATEGORY/INDICATION:
`
`Injection
`DOSAGE FORM:
`IOO pg/mL, 2 mL, in a 2 mL amfioule or vial
`STRENGTHS:
`ROUTE OF ADMINISTRATION:
`DISPENSED:
`
`X Rx
`
`OTC
`
`‘
`
`"
`
`CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOL.WT:
`
`
`
`’
`
`(S)-4.[1-(2.3~dimethylphenyl)ethyl]-
`1H-imidazole hydrochloride
`DEXMEDETOMIDINE HYDROCHLORIDE
`
`
`
`

`

`
`
`NDA 21—038
`
`.
`
`Chemistry Review # l
`
`Page 2 of 33
`
`CONCLUSIONS & RECOMMENDATIONS:
`
`a. No DMF reviews are pending.
`
`b. The validation of the analytical methods is in progress.
`
`@lnspection of the facilities has been completed.
`'W .
`
`'M. ‘
`7 a W
`
`‘
`
`g1,
`
`. d All chemistry related consult reviews, namely themicrobiology and tradename reviews, have
`been completed.
`
`(‘fiul ‘
`
`{'9 The comments and deficiencies listed in the Draft Letter must be conveyed to the Applicantk: ,i
`
`_ D This application is approvablgl'from the chemistry standpoint pending satisfactory resolution
`of the issues relatedW ‘V
`
`.
`
`\3‘
`
`
`
`Michael C. Theodorakis, Ph.D.
`Senior Review Chemist
`
`Albinus M. D'Sa, Ph.D.
`
`Chemistry Team Leader
`
`——l
`
`

`

`REVIEW FOR HFD-17O
`
`OFFICE OF NEW DRUG CHEMISTRY
`
`MICROBIOLOGY STAFF
`
`ADDENDUM TO MICROBIOLOGIST'S REVIEW #1 OF NDA
`November 23,1999
`
`.A.
`
`'
`
`1.
`
`NDA ’-
`
`_
`
`21-038
`
`SEQNSQR
`
`Abbott Laboratories
`
`
`
`demedetomidine HCl) for Infusion
`
`: Sten'le 2 mL vials
`and 2 rnL ampules for nfusion
`
`4. W: Terminal moxst heat by autoclave. The
`ampule presentation is aseptically processed before the autoclave cycle.
`
`' 5.
`
`' W: Sedative
`
`6. W: IS
`
`-
`
`B.
`
`l. W: Deceinber 18, 1998
`
`2. W: N/A
`
`3. W: Microbiologist’s Review #1 dated April 27, 1999,
`Inspection Report (FDA 483) dated March 6, 1999, and letter from Compliance to
`
`4. AW 11/12/99
`
`C. W: The consult request asks for an evaluation of the inspection report of the
`
`m .The inspection evaluated e—x—
`aseptic processing of finished small volume stenle solution products, and resulted1n
`findings of cGMP deviations Consequently, a letter was sent (November 1, 1999) from
`the FDA’s Office ofCompliance to notify the firm that it was not in a state of
`compliance. Microbiologist’s Review #1 ofthe NDA was done by Dr. Patricia Hughes.
`and recommended approval ofthe finished product, which is manufactured at Abbott‘s
`facility in Rocky Mount. NC. Notes concerning the lnvestigator’s findings, Compliance‘s
`
`WT",
`
`.-~
`
`Page I
`
`

`

`
`
`Addendum to Microbiologist's Review #1
`.
`'
`NDA 21-038
`
`
`recommendation, and the Microbiologist‘s review are provided in the “Review Notes"
`that follow.
`
`D. W: The application is recommended for APPROVAL. Additional
`considerations are discussed in section “B. Review Notes”.
`
`./
`
`\ \
`fa
`Davidi—Iussong,Ph.
`.
`‘ 7.7+:
`
`u-‘st‘is
`
`1! /23/Qf
`
`APPEARS nus
`0N omcmuw"
`
`

`

`
`
` DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`PUBLIC HEALTH SERVICE
`
`
`FOOD AND DRUG ADMINISTRATION
`
`
`
` FROM: HFD- I 70 (Division of AnestheticLCriticol Core, and Addiction
`
`REQUEST FOR CONSULTATI
`
`Drug Products),-Dr. Cynthia McCormick
`
`
`. TOIDivision/Ollice): HFD-l60 (Division of Microbiology). Dr. Peter
`’
`‘ey, Porklown Rm IBB-OB
`
`
`TYPE OF DOCUMENT
`DATE OF DOCUMENT
`
`
`
`November 10. 1999
`
`November I, I999
`Conclusion of COMP inspection
`
`
`
`of Dexmedetomidlne locility in
`F—————‘\_—_—
`
`
`
`
` NAME OF DRUG
`PRIORITY CONSIDERATION
`cwsmcmow or DRUG
`
`
`DESIRED COMPLETION DATE
`
`
`Dexmedetomidine
`I-S
`~
`ASAP
`'
`
`
`
`
`
`REASION FOR REQUEST
`
`High
`
`
`
`-
`
`-.
`
`.-
`
` I I i
`
`
`
`
`
`
`D PRE-NDA MEETING
`D NEW PROTOCOL
`D END OF PHASE II MEETING
`. D PROGRESS REPORT
`
`D RESUBMISSION
`E D‘NEW CORRESPONDENCE
`D SAFETY/EFFICACY
`, D DRUG ADVERTISING ~
`
`
`
`D PAPER NDA
`—D ADVERSE REACTION REPORT
`
`
`D CONTROL SUPPLEMENT
`I MANUFACTURING CHANGE/ADDITION
`D MEETING PLANNED BY
`
`
`
` II. BIOMETRICS
`
`I. GENERAL
`
`- -‘
`
`’4... D RESPONSE TO DEFICIENCY LETTER
`.j , D FINAL PRINTED LABELING
`D LABELING REVISION
`D ORIGINAL NEW CORRESPONDENCE
`D FORMULATIVE REVIEW
`D OTHER (SPECIFY BELOW):
`..
`
`
`D TYPE A OR B NDA REVIEW
`
`
`D CHEMISTRY REVIEW
`r-~-oor PHASE ”MEETING
`/\0. C) J
`D PHARMACOLOGY
`
`
`
`o BIOPHARMACEUTICS
`c C\
`lTROLLED STUDIES
`‘1/
`
`
`:1 OTHER (SPECIFY BELOW):
`1,\\
`.-roc0L .REVle
`\
`
`
`
`0 OTHER (SPECIFY BELOW):
`\\\\
`
` III. BIOPHARMACEUTICS
`
`
`
`
`
`D DEFICIENCY LETTER RESPONSE
`D PROTOCOL-BIOPHARMACEUTICS
`D IN-VIVO WAIVER REQUEST
`
`D DISSOLUTION
`D BIOAVAILABILTY STUDIES
`D PHASE IV STUDIES
`
`D PHASE IV SURVEILLANCE/EPIDEMIOLOGY PROTOCOL
`D DRUG USE e.g. POPULATION EXPOSURE. ASSOCIATED, DIAGNOSES
`D CASE REPORTS OF SPECIFIC REACTIONS (List below)
`D COMPARATIVE RISK ASSESSMENT ON GENERIC DRUG GROUP
`
`
`
`
`
`
`D REVIEW OF MARKETING EXPERIENCE. DRUG USE AND SAFETY
`D SUMMARY OF ADVERSE EXPERIENCE
`D POISION RICK ANALYSIS
`
`
`
`
`
`IV. DRUG EXPERIENCE
`
`COMMENTS/SPECIAL INSTRUCTIONS:
`
`
`
`Please review the microbiology~related conclusions of the cGMP inspection of the facility for manufacturing the bulk dmg substance, dexmedetomidine HCI.
`located in Espoo Finland.
`It should be noted that the bulk substance is shipped to US and the drug product, dexmedetomidine HCI injection. is manufactured
`by Abbott Labs and is terminally sterilized. The Abbott Labs facility was tound to be acceptable by Compliance. Please indicate whether or not the approvable
`recommendation of your staff regarding this appliation is still valid. Please note that the SVT product (NDA 20-038) was not evaluated in this establishment
`inspection.
`
`
`
`
`
`é“ n‘tqu”
`
`
`
`
`
`
`
`
`[-IIYOU have any written comments, please provide a copy tor Laura Governale. Regulatory Project Manager. HDF-170 and Joan Fuschet"
`
`'
`
`tURE or REQUESTER
`
`(
`
`;_
`
`' SIGNATURE OF RECEIVER
`
`
`
`

`

`
`
`gf
`3
`‘
`
`aw...‘
`
`..
`DEPARTMENT OF HEALTH & HUMAN SERVICES
`(.
`__
`_
`.
`puauc HEALTH SERVICE
`_.
`h _
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`‘ In
`
`Division of Manufacturing and Product Quality, HFDo320
`_
`‘
`.
`7520 Standish Place
`Rockwlle; Maryland 20855-2737
`
`TELEPHONE:
`FAX:
`
`(301) 594-0093
`(301) 594-2202
`
`-
`
`'
`
`NOV
`
`I
`
`'999
`
`_
`
`Dr. Jyrki Mattila
`President
`
`'
`
`Orion Corporation,
`Orion Pharma
`‘Orionintie 2
`
`02101 Espoo, Finland
`
`—
`
`_
`Dear Mr. Mattila:
`The Food 8t Drug Administration has completed its review of the March 1-6,
`1999 inspection of your sterile pharmaceutical manufacturing facility in Espoo,
`Finland. The inspection revealed significant deviations from current good
`manufacturing practices (CGMP) in the manufacture of sterile
`pharmaceuticals. The deviations were presented to your attention on an FDA-
`483 List of Observations at the close of the inspection. The CGMP deviations
`cause these drug products to be adulterated within the meaning of section
`501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act.
`
`Some notable deficiencies include:
`
`1. No records that equipment was sterilized or disinfected. No record existed
`for materials/equipment including but not limited to: stopper bowl, stopper
`bowl plastic cover, RCS microbial sampler, and scissors.
`
`It should be noted that sterilization and sanitization records are fundamental
`
`to a sterile drug product manufacturing operation. As part of your response to
`this issue, please specifically state whether stopper bowls (and associated
`covers) are sterilized or only disinfected.
`
`2. Lack of reconcilability of vials discarded during the media fill opefation.
`
`Inadequate Studies performed to evaluate laminarity of air in class 100
`3.
`processing zone.
`
`4. Failure to adequately control computer software used to record and process
`data for annualjgeports, complaint handling, raw material weighing, creating
`
`

`

`
`
`Page 2- Orion Pharma, Fl (96l0102)
`
`batch record instructions (in some instances), and control/release of goods
`from raw material through finished stages.
`
`5. A number of instances of failure to maintain either adequate or sufficient
`records, including validation documentation.
`
`For example, autoclave load configurations and placement of thermocouples in
`autoclave chamber were not adequately described in SOPs. As another
`example, your firm did not document which aerosol compound was used for
`performing integrity tests of HEPA filters in the aseptic processing area.
`
`With regard to computers, we note that there was no record of original system
`requirements or design.
`In addition, the previous software version/s/ for
`significant- programs were not retained. Version control should be practiced
`for software developed by firms for use in any CGMP application.
`
`Within your response to this letter, please provide an update on your firm's
`progress toward retaining digital data (observations 23-26). The inspection
`found that many quality control laboratory digital data files were deleted.
`
`6. Change control procedures were inadequate. As an example, significant
`water system changes (e.g., changes in major piping) were not the subject of
`increased testing for purposes of revalidation.
`In addition, when significant
`systems (e.g., air, water, etc.) undergo modifications, the updated
`configuration of the system should be promptly and adequately documented.
`
`7. Water for injection (WFI) sampling was inadequate. Some points of use
`(approximately one-quarter of them) were not sampled, and only three samples
`were taken per week. Please note that at least one sample should be taken
`from the WFI system daily, and. rotation of sampling to agiven WFI takeoff
`point should generally occur more frequently than monthly (as stated in your
`FDA 483 response).
`
`Please clarify each of the above items in your response and address your firm's
`efforts to handle these issues globally.
`Includea timetable of when
`_
`corrections will be completed and supporting documents and translations in
`English. Specifically, we would prefer a report updating the status of each
`commitment (e.g., creation or revision of an SOP; performing training) included in
`your lirm’s April 20 and June 4, 1999 responses.
`
`Finally, we would like to clarify one aspect of FDA 483 observation #20 and
`your associated written response. We consider the person performing the
`
`
`
`

`

`
`
`Page 3. Orion Pharma. Fl (9610102)
`
`validation studies to be responsible for the integrity of data generated.
`However, it is not a specific GMP-requirement that the data muSt be otherwise
`“evaluated" by this specific individual. “Evaluation" can connote an
`assessment or interpretation of the data in order to reach a conclusion on
`process validity. FDA does not require conclusions on the validity of the
`process to be determined by the same person generating the actual data for the
`study. This critical responsibilityis one which FDA expects to be properly
`discharged by specified personnel of the firm including final review and
`approval by responsible officials of the quality control unit.
`
`The CGMP deviations identified above are rim to be considered an all
`
`inclusive liSt of the deficiencies at your facility. F DA inspection are audits
`which are not intended to determine all deviations fror‘h CGMPs that exists at
`'a firm. We récommend that you continually evaluate the overall CGMP
`compliance of your facility
`
`Until FDA has confirmed that your—firm is in CGMP compliance we will not
`recommend approval of any new drug applications for sterile drugs
`manufactured by this facility.
`
`Please acknowledge your receipt Of this letter. Facsimiles may be sent to (301)
`827-0145. You may contact me at (301) 594-0095 with any questions.
`
`Sincerely,
`
`V t. 1% \
`
`Richard L. Friedman
`
`Compliance Officer
`Investigations and Compliance Branch
`
`

`

`

`

`
`
`fun-21.“.
`
`.
`
`é DEPARTIVIENTOFHEALTH& HUMANSERVICES
`“as,"W
`Memorandum
`
`Public Health Service
`
`FoodandDrugAdninisttab’m
`
`December 1, 1999
`DATE:
`FROM: Albinus M.D'Sa, Ph.D.
`
`CD\
`\
`
`_
`
`TO:
`
`NDA file # 21-038
`
`SUBJECT:
`NDA 21-038, CMC review status
`I amiwriting this memo to'docurnent a telcon that occurred yesterday between David Hussong, Ph.D.
`(Acting Assoc. Director of Microbiology, Acting for Perter Cooney, Ph.D.).
`-
`‘
`
`I indicated to Dr. Hussong that the division was concerned and needed clarification on the comment
`made in the consult review. (page 10, fourth paragraph). The review was done by Patrica Hughes,
`Ph.D., who I was informed no longer works in the Division ofMicrobiology. The comment related
`to the asceptic processing prior to the terminal sterilization of the product. The commient stated that
`this process was not validated and the filters have not been validated for microbial retentivity.
`Dr. Hussong, said that the review conclusion are based on the terminal sterilization process and its
`validation. The lack of information in the asceptic processing such as filter retention is not critical.
`so this was not a problem that he was concerned about. The filtration step does not have to be
`validated because the materials are accepted with low bioburden.
`
`I also inquired during the conversation on the status ofthe inspection consult that chemist had sent
`to Peter Cooney. He indicated that it was completed and we should have already received it.
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`APR 3 0199.0
`
`__~
`REVIEW TO HEB-17o _._..
`OFFICE OF NEW DRUG CHEMISTRY
`
`“
`
`MICROBIOLOGY TEAM
`
`MICROBIOLOGIST REVIEW OF A NDA
`
`27 April 1999
`
`A. NDA 21-038
`
`1
`
`-
`
`”
`
`'PRODUCT NAME: "—-« x (dexmedetomidine HCl) for Infusion
`
`APPLICANT:‘V Abbott Laboratories
`
`Sterile aqueous solution in vials and ampoules for injection;
`DOSAGE FORM:
`.. List No. 1638, 2 mL vial, 100 ug/mL and List 3434 2 mL ampoule, 100
`“gm
`METHOD OF STERILIZATION: Terminal sterilization by autoclave -
`PHARMACOLOGICAL CATEGORY: Alpha-2 sedative with analgesic
`properties for use in an intensive care
`setting.
`
`B.
`
`INITIAL APPLICATION DATE:
`
`18 December 1998
`
`'
`
`'
`
`’ ASSIGNED FOR REVIEW:
`
`11 February 1999
`
`C. REMARKS: A microbiology consult was requested to review the terminal
`sterilization process and the sterility test information. The drug product is a sterile
`aqueous solution filled in vials and ampoules. It is intended to be further diluted with
`0.9% sodium chloride prior to intravenous infusibn. ‘
`‘
`
`-
`
`lexmedetomidine
`D. CONCLUSIONS :’ The‘NDA 21“-038,‘whi'chiprovides for.
`HCl) Injection is recommended forapprovalfrom the standpoint of prod ct quality
`microbiology. Please see section E for Review Notes.
`S
`
`
`
`- 0 ’9 7,
`
`Patricia F. Hughes, Ph. D.
`Review Microbiologist
`
`as. .450 a?
`
`
`
`

`

`J
`
`DEPARTIENT OF HEALTH AND HLMAN SERWCES
`PUBLIC HEALTHSERVIOE
`FOOD AND DRUG AWNISTRATION
`
`REQUEST FOR CONSULTATION
`
`1° “WWW”
`“cal Imaging and RadiOPhafinaceutlca' Drug
`'ucts Dr. Peter Cooney HFD-160 Rm. 188-08
`
`
`
`FROM: Michael Theodorakis, REViewing Chemist
`Anesthetic, Critical Care & Addiction Drug Products
`
`~327.7410
`"5:13.170
`
`
`DATE
`February 5. 1999
`
`NAME OF DRUG
`
`NDA No.
`TYPE OF DOCUMENT
`DATE OF DOCUMENT
`21 -038
`NDA
`12-18-98
`'
`
`DESIRED COMPLETION DATE
`CLASSIFICATION OF DRUG
`PRIORITY CONSIDERATION
`
`
`May 30. 1999
` Routine
`
`
`
`
`
`
`
`NAME OF FIRM: ‘ Abbott Laboratories
`REASON FOR REQUEST
`
`(dexmedetomidine HCL)
`Injection
`
`-
`
`-‘
`
`0 NEW PROTOCOL
`0 PROGRESS REPORT
`Cl NEW CORRESPONDENCE
`D DRUG ADVERTISING
`O ADVERSE REACTION REPORT
`0 MANUFACTURING CHANGE/ADDITION
`0 MEETING PLANNED BY
`-
`
`L GENERAL
`
`.ESPONSE TO DEFICIENCY LETTER
`El PRE—NDA MEETING
`.4 FINAL PRINTED LABELING
`\
`:1 END OF PHASE II MEETING
`El LABELING REVISION
`c1 RESUBMISSION
`D SAFETY/EFFICACY
`/ $3 D ORIGINAL NEW'CORRESPONDENCE
`x PAPER NDA \ n FORMULATIVE REVIEW
`c1 CONTROLSUPPLEM”
`\C“ OTHER (SPECIFYBELOW):
`I Q\
`,IOMETRICS
`
`STATISTICAL EVALUATION BRANCH
`'°E A OR B NDA REVIEW
`J OF PHASE II MEETING
`JNTROLLED STUDIES
`CI PROTOCOL REVIEW
`O OTHER (SPECIFY BELOW):
`
`
`
`
`
`
`
`D DISSOLUTION
`CI DEFICIENCY LETTER RESPONSE
`C] BIOAVAILABILTY STUDIES
`D PROTOCOL-BIOPHARMACEUTICS
`
`
`0 PHASE IV STUDIES
`D lN-VIVO WAIVER REQUEST
`
`
`
`IV. DRUG EXPERIENCE
`
`STATISTICAL APPLICATIo . BRANCH. ..
`13 CHEMISTRY REVIEW
`D PHARMACOLOGY
`CI BIOPHARMACEUTICS
`Cl OTHER (SPECIFY BELOW):
`
`0 PHASE IV SURVEILLANCE/EPIDEMIOLOGY PROTOCOL
`D DRUG USE e.g. POPULATION EXPOSURE. ASSOCIATED DIAGNOSES
`0 CASE REPORTS OF SPECIFIC REACTIONS (Us! below)
`Cl COMPARATIVE RISK ASSESSMENT ON GENERIC DRUG GROUP
`
`D REVIEW OF MARKETING EXPERIENCE. DRUG USE AND SAFETY
`[I SUMMARY OF ADVERSE EXPERIENCE
`D POISON RICK ANALYSIS
`
`‘
`
`' V. SCIENTIFIC INVESTIGATIONS
`
`Cl PRECLINICAL
`U CUNICAL
`COM MENTSISPECIAL INSTRUCTIONS:
`_
`
`This is a terminally sterilized small volume injection. Please review the sterilization
`process and sterility testing information.
`
`
`
`I
`
`I
`
`I ‘
`
`'
`
`fInNATI IRF m: RFOUESTER
`\
`
`__..
`E: 1;"I “‘1’
`...IcnaeI u. meo- . KIS, r.n.u.
`SIGW‘:h "5":_—nm:"g“r_: 29
`‘
`9/“
`
`W"
`
`METHOD OF DELIVERY (Check one)
`U MAIL
`D HAND
`
`SIGNATURE OF DELIVERER
`
`
`
`

`

`O3-DEC-1999
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Page
`
`i of
`
`[\J
`
`NDA 21038/000
`Application:
`Stamp: ~1-8-DEC-1998 Regulatory Due:
`Applicant:
`ABBOTT LABS
`200 ABBOTT PARK RD D389 BLDG A '
`ABBOTT PARK, IL 600643537
`
`lS-JAN-2000
`
`‘
`
`Org Code: 170
`IS
`Priority:
`19-NOV-]999
`District Goal:
`Action Goal:
`Brand Name: ’V. EXMEDETOMIDINE
`HCL)100MCG/ML I
`Established Name:
`
`GenericName: DEXMEDETOMIDINE HCL
`Dosage Form:
`INJ
`(INJECTION)
`Strength:
`100 MCG/ML
`
`* —
`
`301-827-7410 , Project Manager
`(HEB-170)
`S. SAMANTA
`FDA Contacts:
`-
`M. THE’ODORAKIS (HEB-170)
`301-827-7425 , Review Chemist
`.
`A. D SA
`(HFD-170)
`301-827-7443 , Team Leader
`
`Overall Recommendation:
`
`ACCEPTABLE on 19-NOV-1999 by M. EGAS (HFD-322)301-594-0095
`
`Establishment: 1021343
`DMF No: "K
`ABBOTT LABORATORIES
`AADA No:
`HWY 301 NORTH
`
`ROCKY MOUNT, NC 27804
`
`OAI Status: NONE
`SVT
`Profile:
`Last Milestone: OC RECOMMENDATION
`Milestone Date
`20-MAY-1999
`
`Decision:
`
`ACCEPTABLE
`
`Reason:
`
`DISTRICT RECOMMENDATION
`
`Responsibilities: FINISHED DOSAGE
`.
`MANUFACTURER
`
`—M_—__—h_—_—_——_—“ -.
`Establishment: 1411365
`DME No: A
`_
`ABBOTT LABORATORIES
`AADA NO:
`1401 14TH & SHERIDAN ROAD
`
`NORTH CHICAGO, IL 60064
`
`OAl Status: NONE
`Profile: CTL
`Last Milestone: OC RECOMMENDATION
`Milestone Date
`03-FEB-1999
`Decision:
`ACCEPTABLE
`
`Reason:
`
`BASED ON PROFILE
`
`Responsibilities: FINISHED DOSAGE STABILITY
`TESTER
`
`.
`
`Establishment: 9610102
`ORION CORP LTD
`FERMION KOIVUMANKKAANTIE 6
`ESPOO, , P]
`
`DMF No:
`AADA No:
`
`/’\/—
`
`‘
`
`OAI Status: NONE
`Profile: CSS
`Last Milestone: OC RECOMMENDATION
`Milestone Date
`19-Nov-1999
`
`Responsibilities: DRUG SUBSTANCE
`MANUFACTURER
`
`—
`
`—
`
`
`
`

`

`o3-DEC-1999
`
`‘
`
`FDA CDER EES
`ESTABLISHMENT EVALUATION REQUEST
`SUMMARY REPORT
`
`Page
`
`2 of
`
`I‘J
`
`Decision:
`
`ACCEPTABLE
`
`_
`
`Reason:
`
`DISTRICT RECOMMENDATION
`
`
`
`APPEARS THIS WAY
`
`0N ORIGINAL
`
`

`

`M E M O R A N D U M »
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICES
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Date:
`
`June 451999
`
`.- ~-
`
`T'oi
`
`Food~ and Drug Administration, Pre-apprOval Laboratories
`
`1" Laboratory
`
`Division of Testing and Applied Analytical Development, HFD-920
`1114 Market Street, Room 1002
`
`St. Louis, MO 63101
`Attention: Harry Coffman
`
`2"d Laboratog
`
`Philadelphia District Laboratory, HFR-MA160
`US Customhouse
`-
`
`2nd and Chestnut Streets, Room 900
`
`Philadelphia, PA 19106
`Attention: Nicholas Falcone
`
`From:
`
`Michael Theodorakis, Ph.D. Senior Review Chemist, HFD-170,- I” a T
`Division of Anesthetic, Critical Care, and Addiction Drug Products, CDE
`
`6/4/7 ¢
`R
`
`Through:
`
`M {7
`Albinus D'Sa, Ph.D., Chemistry Team Leader, HFD-170,
`Division of Anesthetic, Critical Care, and Addiction Drug Products, CDB
`
`Subject:
`
`Laboratory Assignments for NDA Methods Validation (MV)
`
`NDA No:
`
`21-038
`
`Product:
`
`‘M' .' (dexmedetomidine HCl) lnjection
`
`Applicant:
`
`Abbott Laboratories,
`200 Abbott Park Road
`
`Abbott Park, IL 600064-3537
`Attn: Thomas F. Willer, Ph.D., Assistant Director, Regulatory Affairs,
`tel. 847-937-6845
`'
`
`

`

`Please find attached an amendment to NDA 21-038 that contains revisions for the following
`analytical procedures:
`
`a. 74762 Dexmedetomidine HCl
`b. C-168l Deterrnination and Identification of Deirn'edetomidine and Related Substances
`in Bulk Drug and Injection.
`
`.This amendment should become part of the MV package for NDA 21-038 that was mailed to
`your labs on March 17,1999.
`
`Enclosures
`
`cc:
`
`Original NDA 21-038
`HFD-l 70 Division File
`
`1 —
`
`APPEARS THIS WAY
`0N ORIGINAL
`
`

`

`. Application
`
`Establishments
`
`Establishment
`; CFN
`Name
`
`‘
`
`Overa" Compliance:
`Date
`
`Alert '
`
`‘—‘-Last<:ompnance
`:Status,..-Date
`
`'Code Name
`
`‘
`" .'
`
`"
`
`"
`w -
`
`_
`
`- l__'_' I
`
`'nll'hbb_'
`
`OAl
`
`.Ji
`1%;
`
`g'1:
`
`L1:
`
`APPEARS nus WAY
`on ORIGINAL
`
`

`

`M E M O R A N D U M
`
`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`PUBLIC HEALTH SERVICES
`
`FOOD AND DRUG ADMINISTRATION
`
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`Date:
`
`-
`
`June 4, .1999
`
`I
`
`-
`
`To:
`
`'
`
`Food and Drug Administration, Pre-approval Laboratories
`
`1" Laboratory
`
`Division of Testing and Applied Analytical'Development, HFD-920
`1114 Market Street, Room 1002
`
`'
`
`St. Louis, MO 63101
`Attention: Harry Coffman
`
`2“d Laboratog
`
`Philadelphia District Laboratory, HFR—MA160
`US Customhouse
`
`2nd and Chestnut Streets, Room 900
`
`Philadelphia, PA 19106
`Attention: Nicholas Falcone
`
`From:
`
`Through:
`
`Michael Theodorakis, Ph.D. Senior Review Chemist, HFD-17O,~ /’7 0T 6/4/7 /
`
`~
`
`(
`
`Division of Anesthetic, Critical Care, and Addiction Drug Products, CDER
`.
`\
`7 /UI' I)! A
`Albinus D'Sa, Ph.D., Chemistry Team Leader, HFD-170,
`M { ‘
`~‘/‘//? 1}
`Division of Anesthetic, Critical Care, and Addiction Drug Products, CDER 6
`
`Subject:
`
`Laboratory Assignments for NDA Methods Validation (MV)
`
`NDA No:
`
`21-038
`
`Product: /-\
`
`\dexmedetomidine HCI) Injection
`
`Applicant: Abbott Laboratories,
`200 Abbott Park Road
`
`Abbott Park, IL‘ 600064-3537
`Attn: Thomas F. Willer, Ph.D., Assistant Director, Regulatory Affairs,
`tel. 847-937-6845
`
`
`
`

`

`Please-find attached an amendment to NDA 21-038 that contains revisions-for the following
`analytical procedures:
`
`a. 74762 Dexmedetomidine HCl
`
`b. C-l681 Determination and Identification of Dexmedetomidine and Related Substances
`in Bulk Drug and Injection.
`
`This amendment should become part of the MV package for NDA 21-038 that was mailed to
`your labs on March‘1-7, 1999.
`
`Enclosures
`
`cc:
`
`Original NDA 21-038
`HFD—l 70 Division File
`
`APPEARS THIS WAY
`on ORlGlNAL
`
`
`
`