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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
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`APPLICATION NUMBER:
`22-264
`22-264
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`APPLICA TION NUMBER:
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`CHEMISTRY REVIEW(S)
`CHEMISTRY REVIEW! S}
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`CHEMISTRY REVIEW
`
`NDA 22-264
`
`
`INVEGA® SUSTENNA
`(paliperidone palmitate extended release injectable suspension)
`
`
`Janssen Pharmaceutica N.V.
`
`
`Review #2
`
`David J. Claffey, Ph.D.
`ONDQA
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`CHEMISTRY REVIEW
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`Table of Contents
`
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`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................3
`
`The Executive Summary .........................................................................................8
`
`I. Recommendations .......................................................................................................................8
`A. Recommendation and Conclusion on Approvability.......................................................................8
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable...................................................................................................8
`
`II. Summary of Chemistry Assessments.........................................................................................8
`A. Description of the Drug Product(s) and Drug Substance(s) .............................................................8
`B. Description of How the Drug Product is Intended to be Used........................................................13
`C. Basis for Approvability or Not-Approval Recommendation..........................................................13
`
`III. Administrative.........................................................................................................................14
`A. Reviewer’s Signature......................................................................................................................14
`B. Endorsement Block.........................................................................................................................14
`C. CC Block ........................................................................................................................................14
`
`Chemistry Assessment.......................................................................................... 15
`S
` DRUG SUBSTANCE...................................................................................................................22
`P
` DRUG PRODUCT........................................................................................................................30
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1 ..................................34
`A. Labeling & Package Insert ............................................................................................................34
`B. Environmental Assessment Or Claim Of Categorical Exclusion ...................................................34
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`Chemistry Review Data Sheet
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`
`
`
`1. NDA 22-264
`
`
`2. REVIEW #:2
`
`
`3. REVIEW DATE: 20 JUL 2009
`
`
`4. REVIEWER: David J. Claffey, PhD
`
`
`
`5. PREVIOUS DOCUMENTS:
`
`
`Previous Documents
`IND 67,356
`Original NDA
`Amendment (BC)
`Amendment (BC)
`Amendment (BL)
`Amendment (BC)
`
`
`
`
`
`
`
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`
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`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`Amendment N-0026
`Amendment N-0028
`Amendment N-0033
`Amendment N-0038
`Amendment N-0039
`Amendment N-0040
`Amendment N-0041
`
`
`
`
`
`
`Page of 55 3
`
`Document Date
`6 MAY 2003
`26 OCT 2007
`26 MAY 2008
`13 JUN 2008
`2 JUL 2008
`11 JUL 2008
`
`Document Date
`3 FEB 2009
`
`24 FEB 2009
`22 MAY 2009
`16 JUL 2009
`17 JUL 2009
`20 JUL 2009
`20 JUL 2009
`
`
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`
`
`
`
`
`Name:
`
`Address:
`
`Representative:
`
`Telephone:
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Janssen, L.P.
`Johnson & Johnson Pharmaceutical Research &
`Development, LLC
`Office 12607, 1125 Trenton-Harbourton Road,
`Titusville, NJ 08560
`
`
`Kelly Ward (for CMC related issues)
`
`609-730-2056
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`
`a) Proprietary Name: INVEGA® SUSTENNA
`b) Non-Proprietary Name (USAN): Paliperidone palmitate
`c) Code Name/# (ONDC only): JNJ16977831; R092670
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 2
`• Submission Priority: S
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`
`10. PHARMACOL. CATEGORY: Antipsychotic
`
`
`
`11. DOSAGE FORM:
`
`
`12. STRENGTH/POTENCY: 39 mg, 78 mg, 117 mg, 156 and 234 mg of
`paliperidone palmitate (data for
` strength was provided but applicant is not
`seeking approval for this strength at this time).
`
`
`
`13. ROUTE OF ADMINISTRATION: Intramuscular
`
`
`
`
` extended release injectable suspension
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`Page of 55 4
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`(b) (4)
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`14. Rx/OTC DISPENSED: _x__Rx ___OTC
`
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
` SPOTS product – Form Completed
`
` x Not a SPOTS product
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`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`(9RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-
`tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl hexadecanoate
`(±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl4-oxo-
`4H-pyrido[1,2-a]pyrimidin-9-yl hexadecanoate
`
`Empirical formula: C39H57FN4O4
`
`
`
`Molecular weight: 664.89
`
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`A. DMFs:
`
`
`
`DMF
`#
`
`TYPE HOLDER
`
`ITEM
`REFERENCED
`
`CODE1
`
`STATUS2
`
`DATE
`REVIEW
`COMPLETED
`
`COMMENTS
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`Page of 55 5
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`II
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`20902
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`18915
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`II
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`III
`III
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`III
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`III
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`Janssen
`Pharmaceutic
`a,
`N.V.
`
`Janssen
`Pharmaceutic
`a,
`N.V.
`
`Paliperidone
`palmitate as
`manufactured in
`Beerse and Cork,
`Ireland
`Belgium
`Paliperidone
`(R076477
`“crude”) as
`manufactured
`in Beerse, Belgium
`
`
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`1
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`1
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`1
`1
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`3
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`1
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`
`Adequate
`
`07/18/2008
`
`T. Ocheltree
`David Claffey
`
`Adequate
`
`07/14/2008
`
`T. Ocheltree
`
`
`Adequate
`Adequate
`
`
`
`07/14/2008
`
`David Claffey
`By T. Ocheltree
`
`Adequate
`
`06/25/2008
`
`By Y. Sun
`
`Adequate
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`06/03/2008
`
`By J. Metcalfe
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`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`3 – Reviewed previously and no revision since last review
`4 – Sufficient information in application
`5 – Authority to reference not granted
`6 – DMF not available
`7 – Other (explain under "Comments")
`
` 2
`
` Adequate, Inadequate, or N/A (There is enough data in the application, therefore the DMF did
`not need to be reviewed)
`
`B. Other Documents: N/A
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`Page of 55 6
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`(b) (4)
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`(b) (4)
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`18. STATUS:
`
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`ONDC:
`CONSULTS/ CMC
`RELATED
`REVIEWS
`Biometrics
`EES
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`Pharm/Tox
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`Biopharm
`LNC
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`CDRH
`Microbiology
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`
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`RECOMMENDATION
`
`DATE
`
`REVIEWER
`
`
`Acceptable
`Acceptable
`Approval
`recommendation
`acceptable
`Provided
`recommendation
`Acceptable
`Approval
`recommendation
`
`
`
`Shawnte Adams
`15 APR 2008
`E Johnson
`2 JUL 2009
`17 JUN 2009 Elzbieta Chalecka-Franaszek
`
`01-AUG-2008
`
`
`
`John Duan
`Refer to review
`
`6 MAY 2009 William Burdick
`30 JUN 2008
`John Metcalf
`4 May 2009
`(Cork Site)
`
`
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`Page of 55 7
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`CHEMISTRY REVIEW
`Executive Summary Section
`The Chemistry Review for NDA 22-264
`
`The Executive Summary
`
` I. Recommendations
`
`
`
`
`A. Recommendation and Conclusion on Approvability
`
`Recommend approval from a CMC perspective.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or
`Risk Management Steps, if Approvable
`
`On 20 JUL 2009 (N-0041) the applicant committed to adding “a clearly visible fill line to the
`syringe so that the health care provider can ensure that the syringes contain the required volume
`of suspension prior to administration and that no gross leakage or evaporation of the syringe
`contents has occurred during storage or shipping”.
`
`II. Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`Paliperidone is a selective, monoaminergic antagonist that exhibits the characteristic dopamine
`type 2 (D2) and serotonin (5-hydroxytrptamine [5-HT]) type 2A (5HT2A) antagonism of the
`newer second generation, antipsychotic drugs.
`
`Drug Product
`Paliperidone palmitate suspension for injection (F013) was developed as a monthly
`intramuscular injectable suspension for the treatment of schizophrenia. Each milliliter of
`paliperidone palmitate (156 mg/mL) is equivalent to 100 mg/mL of paliperidone. The drug
` and
`product was developed in six dosage strengths: 39 mg, 78 mg, 117 mg, 156 mg,
`234 mg of paliperidone palmitate (equivalent to 25 mg, 50 mg, 75 mg, 100 mg,
` and 150
`mg of paliperidone, respectively). This application proposes the marketing of all
`
`strength. The drug product is packaged in
` transparent cyclic olefin
`copolymer (COC) syringes and marketed as kit containing two needles for administration (a 22-
`g, 1½-inch safety needle and a 23-g, 1-inch safety needle).
`
`
`
`
`The extremely low solubility of paliperidone palmitate allows the formulation of an extended
`release product where the isotonic aqueous buffer solvent penetrates the muscle tissue and the
`undissolved paliperidone palmitate particles are localized at the site as a poorly soluble
`agglomerate. Paliperidone palmitate is stated to dissolve slowly after intramuscular injection
`before being hydrolyzed to paliperidone and absorbed into the systemic circulation.
`
`Stability data provided in the previous review cycle support a 24 month expiry period.
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`CHEMISTRY REVIEW
`Executive Summary Section
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`Drug Substance
`Paliperidone palmitate (R092670 drug substance) is the palmitate ester of paliperidone
`(R076477), the major active metabolite of risperidone. It is practically insoluble in aqueous
`media over a broad pH range. This low solubility allows the drug substance to be formulated as a
`suspension for intramuscular injection that provides an extended release profile that is a function
`of drug substance particle size. The drug substance particle size is controlled by the
`
` executed during the drug product manufacturing process to
`
`
`
` have been demonstrated to not impact drug product performance.
`All drug substance physiochemical information and manufacturing process information is
`referenced to DMF 20902.
`
`Summary of CMC related review issues addressed in the course of this review
`cycle:
`
`Complete response issues:
`
`
` previously found deficient. Holder resolved these
`CR #1: DMF
` for
`deficiencies to the satisfaction of the CDRH reviewer. It should be noted that the
`applicant committed to adding a fill line to the syringe barrel within 12 months of
`approval of this application (N-0041).
`
`CR #2: Strength needs to match the established name: The Division determined in
`consultation with the CDER Labeling and Nomenclature Committee and DMEPA that
`the strengths should be expressed in terms of the paliperidone palmitate rather than
`paliperidone. The applicant agreed to this change (labeling received 16 JUL 2009).
`Although many examples exist in approved products of name-strength mismatches and of
`the incomplete name of an ester being part of the established name, this decision is part
`of the current Agency policy to implement a uniform and consistent policy on this matter.
`
`CR#3: Genotoxic impurities issue: This issue was resolved by re-evaluation of the data
`by this reviewer and through the applicant agreeing to add a test for
`
` to the drug substance specification with a combined limit of
` ppm.
`
`
`CR#4: Addition of a specification for
` to the drug product specification. This
`issue was resolved by the applicants demonstration that their addition of citric acid
` through the expiry period.
`
`
`CR#5: The syringe barrel should contain calibrated markings to indicate the appropriate
`volume of the drug product in the syringe and allow for partial doses to be given from the
`syringe: this issue was resolved when the division agreed in the 28 NOV 2008 meeting
`that calibration markings would not be necessary (see meeting notes). A more detailed
`response regarding the addition of a fill line on the syringe barrel was provided in the 22
`
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`CHEMISTRY REVIEW
`Executive Summary Section
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`
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`MAY 2009 amendment (detailed response to IR#6 and summary of fill line issue on next
`page).
`
`CR#6: A transparent label that allows for the viewing of the syringe calibration marks
`and drug product should be used for labeling of the syringes. As was agreed upon in
`response to CR#5, the calibrated markings would not be required, but the Agency
`requested that a fill line be added to the syringe barrels within 12 months of marketing
`approval. The applicant committed to doing so (email16 JUL 2009, amendment N-
`0041).
`
`
`Other CMC-related issues encountered during this review cycle:
`
`
`
`
`• Summary of genotoxin control issue: The CR letter included a request by the previous
`CMC reviewer (Dr. Terrence Ocheltree) to limit the levels of known genotoxins
`and
` to a level of
` ppm. This corresponded to a maximum daily exposure of
` During the course of this review cycle the applicant proposed amending the
`application with an additional 150 mg strength – therefore the recommended limit for
`genotoxins was lowered to
` ppm so that the maximum patient daily exposure would
`remain at the
`. The applicant proposed carrying out testing for genotoxin
` in the first ten commercial scale drug substance batches of intermediate ‘crude’
`drug substance then deleting this test if levels remained at acceptable levels. The
`applicant describes their “science-based” “criticality analysis” approach to determine
`critical steps and controls for drug substance manufacturing. This criticality analysis was
`supported by a “detailed knowledge of the origin and fate of impurities, including
`potentially genotoxic impurities”. However this ‘detailed knowledge” apparently did not
`include consideration of the
`of
` until the question was
`raised by the Agency in the 24 APR 2009 information request. One would assume that
`this should have been part of the most basic ‘criticality analysis’. The data provided did
`generally demonstrate that the synthetic process is capable of reducing levels of some or
`all of the genotoxin at laboratory and pilot scale. Three lots at commercial scale also
`showed levels of
` ppm of genotoxins. Although the latter are the most convincing
`data, it was in this reviewers evaluation that the experience to date remains limited and
`does not account for typical variations in the manufacturing environment (e.g. personnel
`and process variability). Further, the risk associated with these impurities is high as the
`harm that they have the potential to cause is both high and not immediately detectable by
`the patients. The burden on the applicant to test for these known genotoxins does not
`appear to be high relative to this risk. In this reviewer’s re-evaluation of the applicants
`responses and taking into consideration the synthetic process and the likely fate of
` and
` we requested that the applicant control (at drug substance release)
` and its
` to a combined level of
` ppm. The applicant accepted
`this recommendation in the 16 JUL 2009 amendment (N-0038).
`
`• Dosage form designation issue: the applicant proposed using
`the dosage form designation in the established name. This is in line with the other
`approved drug in this class of anti-psychotic depots – Risperdal Consta (risperidone)
`
` as
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`Page of 55 10
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`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
` However in the Agency’s attempt to implement a more uniform and
`consistant policy in this matter, the Labeling and Nomenclature Committee
`recommended that the dosage form designation ‘extended-release injectable suspension’
`be used. “Injectable Suspension” is one of five acceptable dosage form designations
`listed in USP <1> and “extended release” is the only available modifier to indicate its
`prolonged release in the CDER Data Standard Manuel (DSM) . This recommendation
`was conveyed to the applicant during labeling negotiations. The applicant proposed the
`used of
` as there was no precedent in USP or DSM to use
`“extended release injectable suspension”. Further, they raised the possibility that if
`“extended release” were used that confusion would exist with the marketed INVEGA
`(paliperidone) extended-release tablets. The Agency acknowledged that “extended-
`release injectable suspension” is not mentioned in USP - as a monograph has not yet been
`produced for the single marketed product that uses this dosage form designation i.e.
`Vivitrol (naltrexone for extended release injectable suspension). In an attempt to
`differentiate the two “paliperidone” containing extended-release products, modifications
`of the propriatory name or the carton labels will be carried out in consultation with
`DMEPA (internal meeting 20 JUL 2009). The applicant accepted the use of the
`recommended dosage form designation (telcon 17 JUL 2009).
`
`•
`
`
`
`• Syringe Fill line issue: The applicant was asked to add a fill line to the syringe barrels.
`
`
`
`
`
`
` However these controls are not capable of detecting vials that leak after
`product release, either through a defect in the syringe, the plunger or the stopper. Such
`gross leaks may be detectable by the health care provider as the presence of white
`precipitate should be obvious. However, small leaks that result in leakage and/or
`evaporation of the water within the suspending medium would not be readily detected by
`the health care provider if a fill line were not present and the vial contents not visible.
`Further, such leaks could also result in microbial contamination of the drug product. It
`
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`CHEMISTRY REVIEW
`Executive Summary Section
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`
`should be stressed that data from batch release and stability studies provide no evidence
`that such leaks will routinely occur, however the risk to the patient is high as the
`detectability of such faults is low and severity of harm is high when one considers the
`indication and the relatively long period between treatments. It should be stressed that
`there are no known unique quality defects associated with this product above and beyond
`that of, for example, a typical tablet dosage form. Even in a six sigma process several
`defects per million are allowable, however, the end user generally has the opportunity to
`reduce this risk of quality defects further if a tablet appears cracked, speckled, or off-
`color. A clearly visible fill line will offer the end user of this product that same
`opportunity.
`It should be noted that in this reviewers non-exhaustive search of approved prefilled
`syringe products, all possessed either a fill line or graduations. Most products contained
`instructions for the health care provider to check that the level of liquid in the syringe is
`at or close to a fill line, or that it should be between two fill lines. Prefilled syringes are
`likely to occupy an increasing share of the US parenteral dosage form market due to their
`convenience, less waste of drug substance involved and technology-driven reductions in
`the cost of their production. Should this product have been approved as the applicant
`proposed, it would appear to be the first approved prefilled syringe without a fill line.
`Considering the nature of the proposed indication and the relatively lengthy time between
`administrations this reviewer does not consider the justifications provided for the absence
`of a fill line to be sufficient to set such a precedent. On 20 JUL 2009 (N-0041) the
`applicant committed to adding “a clearly visible fill line to the syringe so that the health
`care provider can ensure that the syringes contain the required volume of suspension
`prior to administration and that no gross leakage or evaporation of the syringe contents
`has occurred during storage or shipping”.
`
`
`
`
`
`
`
`
`• The applicant amended DMF 20902 to include the Cork site as a manufacturing site for
`“sterile grade” drug substance. Previously the Cork site manufactured the intermediate
`“crude” grade drug substance. This amendment was found to be acceptable by this
`reviewer. The Office of Compliance issued an ‘acceptable’ recommendation on 2 JUL
`2009.
`
`• Proposed marketing of the 234 mg dosage strength. This was found acceptable from a
`CMC perspective.
`
`• Clarification of accepted dissolution acceptance criteria: The CR letter contained the
`biopharm reviewer’s request that the applicant accept a version of the dissolution
`specification that lacked the initial 1.5 minute time point. This time point appeared to
`have been omitted as it was not part of the IVIVC as evaluated by the biopharm reviewer,
`but was a quality control to protect against ‘dose dumping’. The applicant agreed to
`accept this incomplete dissolution specification as part of their complete response.
`Clarification was sought from the applicant on this issue. They stated (telecon with PMQ
`Don Henry 14 JUL 2009) that the 1.5 minute time point was still in place and that the
`drug product specifications are unchanged from those proposed in the initial submission
`
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`Page of 55 12
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`CHEMISTRY REVIEW
`Executive Summary Section
`
`
`
`
`(Attachment 2 of this review). This adequately resolves this issue. We recommend that
`the following complete dissolution method be included in the action letter:
`
`Parameter
`Apparatus type:
`Media:
`Volume:
`Temperature:
`Frequency:
`Sampling Times:
`Acceptance
`Criteria:
`
`
`Analysis
`
`Dissolution Method and Specifications
`USP Type II (paddle)
`0.001 M HCl containing 0.489% Polysorbate 20 (Tween®20)
`900 ml
`25 ± 0.5 °C
`50 rpm
`1.5, 8, 20, and 45 minutes
`1.5 minutes NMT % of Label Claim
`8 minutes
` of Label Claim
`20 minutes
` of Label Claim
`45 minutes
` of Label Claim
`HPLC UV detection
`
`
`
`B. Description of How the Drug Product is Intended to be Used
`Treatment is initiated with a dose of 234 mg on treatment day 1 and 156 mg one week later,
`both administered in the deltoid muscle. The recommended monthly maintenance dose is
`117 mg; some patients may benefit from lower or higher maintenance doses within the
`recommended range of 39 mg to 234 mg based on individual patient tolerability and/or
`efficacy. Following the second dose, monthly maintenance doses can be administered in
`either the deltoid or gluteal muscle.
`The product is administered by intramuscular injection. For deltoid injection, a 1 ½-inch
`22G needle is recommended for patients ≥ 90 kg (≥ 200 lb) or a 1-inch 23G needle is
`recommended for patients < 90 kg (< 200 lb). For gluteal injection, a 1 ½-inch 22G needle
`is recommended regardless of patient weight.
`
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`C. Basis for Approvability or Not-Approval Recommendation
`
`All outstanding CMC related issues contained in the CR letter and the information
`requests of 24 APR 2009 and 8 JUL 2009 have been resolved. DMF 20902 for the
`drug substance manufacture and DMF
` for the
` were found to be
`acceptable. The applicant accepted the proposed changes to the established name,
`labeled strengths and the control of genotoxic impurities. The Office of Compliance
`issued an acceptable recommendation on 2 JUL 2009. On 20 JUL 2009 (N-0041) the
`applicant agreed with the Agency recommendation to add “a clearly visible fill line to
`the syringe so that the health care provider can ensure that the syringes contain the
`required volume of suspension prior to administration and that no gross leakage or
`evaporation of the syringe contents has occurred during storage or shipping”.
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`CHEMISTRY REVIEW
`Executive Summary Section
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`III. Administrative
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`A. Reviewer’s Signature
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`B. Endorsement Block
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`ChemistName/Date: Same date as draft review
`ChemistryTeamLeaderName/Date
`ProjectManagerName/Date
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`C. CC Block
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`41 pp withheld immediately following this page as (b)(4) CCI/TS.
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`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`David Claffey
`7/22/2009 10:18:28 AM
`CHEMIST
`
`Thomas Oliver
`7/22/2009 11:05:08 AM
`CHEMIST
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`CHEMISTRY REVIEW
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`NDA 22-264
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`INVEGA® SUSTENNA (paliperidone palmitate) Injection
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`Janssen Pharmaceutica N.V.
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`Terrance Ocheltree, R.Ph., Ph.D.
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`Office of New Drug Quality Assessment
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`CHEMISTRY REVIEW
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`Table of Contents
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`Table of Contents .........................................................................................................2
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`Chemistry Review Data Sheet.....................................................................................3
`
`The Executive Summary .............................................................................................7
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`I. Recommendations..........................................................................................................................7
`A. Recommendation and Conclusion on Approvability............................................................................ 7
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements, and/or Risk
`Management Steps, if Approvable........................................................................................................ 7
`
`II. Summary of Chemistry Assessment ..............................................................................................7
`A. Description of the Drug Product(s) and Drug Substance(s) .................................................................. 7
`B. Description of How the Drug Product is Intended to be Used............................................................... 8
`C. Basis for Approvability or Not-Approval Recommendation................................................................. 8
`
`III. Administrative...............................................................................................................................9
`A. Reviewer’s Signature............................................................................................................................. 9
`B. Endorsement Block................................................................................................................................ 9
`C. CC Block............................................................................................................................................... 9
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`Chemistry Assessment...............................................................................................10
`
`I. Review of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body of Data.............10
`S DRUG SUBSTANCE [Paliperidone palmitate, Janssen Pharmaceutica, N.V.] .................................... 10
`P DRUG PRODUCT [Paliperidone Palmitate Suspension for Injection, Johnson & Johnson]................ 12
`P.2 Pharmaceutical Development ..................................................................................................................... 14
`P.3 Manufacture................................................................................................................................................ 32
`P.4 Control of Excipients.................................................................................................................................. 41
`P.5 Control of Drug Product............................................................................................................................. 41
`P.6 Reference Standards or Materials............................................................................................................... 54
`P.7 Container Closure System .......................................................................................................................... 54
`P.8 Stability ...................................................................................................................................................... 58
`A APPENDICES....................................................................................................................................... 63
`R REGIONAL INFORMATION.............................................................................................................. 63
`
`II. Review of Common Technical Document-Quality (Ctd-Q) Module 1.........................................64
`A. Labeling & Package Insert ................................................................................................................... 64
`B. Environmental Assessment or Claim of Categorical Exclusion ......................................................... 67
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`Chemistry Review Data Sheet
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`1. NDA 22-264
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`2. REVIEW #1
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`3. REVIEW DATE: 10-AUG-2008
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`4. REVIEWERS: Terrance Ocheltree, R.Ph., Ph.D.
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`5. PREVIOUS DOCUMENTS:
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`Previous Documents
`IND 67356
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`Document Date
`05/06/2003
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`Document Date
`10/26/2007
`05/29/2008
`06/13/2008
`07/02/2008
`07/11/2008
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`
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`6. SUBMISSION(S) BEING REVIEWED:
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`Submission(s) Reviewed
`Original (CMC)
`Amendment (BC)
`Amendment (BC)
`Amendment (BL)
`Amendment (BC)
`
`
`
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`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`Address:
`
`Name: Janssen, L.P.
`Johnson & Johnson Pharmaceutical Research &
`Development, LLC
`Office 12607, 1125 Trenton-Harbourton Road,
`Titusville, NJ 08560
`Kelly Ward (for CMC related issues)
`Cross-Pharma CMC Regulatory Affairs
`e-mail: kward1@prdus.jnj.com
`Telephone: 609-730-2056 (phone)
`609-730-2706 (fax)
`
`Representative:
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`8. DRUG PRODUCT NAME/CODE/TYPE:
`
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`a) Proprietary Name: INVEGA® SUSTENNA
`Non-Proprietary Name (USAN): Paliperidone palmitate
`Code Name/# (ONDC only): JNJ16977831; R092670
`b) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 2
`• Submission Priority: S
`
`
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`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
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`10. PHARMACOL. CATEGORY: Antipsychotic
`
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`11. DOSAGE FORM:
`
`
`12. STRENGTH/POTENCY: 39 mg, 78 mg, 117 mg, and 156 mg of paliperidone
`palmitate, equivalent to 25 mg, 50 mg, 75 mg, and 100 mg of paliperidone,
`respectively
`
` Suspension for Injection
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`13. ROUTE OF ADMINISTRATION: Intramuscular injection
`
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`14. Rx/OTC DISPENSED: _X_Rx ___OTC
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`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
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` SPOTS product – Form Completed
`
` X Not a SPOTS product
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`
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`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`(9RS)-3-[2-[4-(6-Fluoro-1,2-benzisoxazol-3-yl)piperidin-1-yl]ethyl]-2-methyl-4-oxo-6,7,8,9-
`tetrahydro-4H-pyrido[1,2-a]pyrimidin-9-yl hexadecanoate
`(±)-3-[2-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]ethyl]-6,7,8,9-tetrahydro-2-methyl-
`4-oxo-4H-pyrido[1,2-a]pyrimidin-9-yl hexadecanoate
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`Page 4
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`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
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`The empirical formula is: C39H57FN4O4
`
`The molecular weight is: 664.89
`
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`A. Supporting DMFs:
`
`DMF # TYPE
`20902
`II
`
`HOLDER
`Janssen
`Pharmaceutica,
`N.V.
`Janssen
`Pharmaceutica,
`N.V.
`
`ITEM REFERENCED
`