`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`203214Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`DATE:
`
`TO:
`
`FROM:
`
`
`
`16-AUG-2012
`
`N203214 File
`
`Craig M. Bertha, Ph.D.
`Chemist
`ONDQA, Division III, Branch VIII
`
`
`
`MEMORANDUM: DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC
`HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`THROUGH: Prasad S. Peri, Ph.D.
`
`
`Branch Chief
`
`
`ONDQA, Division III, Branch VIII
`
`SUBJECT: CMC review of label and labeling revisions, EES status, and overall CMC
`recommendation for NDA 203214
`
`
`SUMMARY:
`The CMC sections of the package insert and the carton and container labels were reviewed (see
`review dated 02-AUG-2012). The comments were sent to the firm in a telephone facsimile on
`06-AUG-2012. The applicant submitted a revised package insert and revised container labels on
`13-AUG-2012, and 14-AUG-2012, respectively. These items are the subject of the first part of
`this review.
`
`Package Insert - Comments of 06-AUG-2012
`
`1. Revise the DOSAGE FORMS AND STRENGTHS section of the package insert to include the
`information required by 21 CFR 201.57(c)(4)(ii), rather than referencing the DESCRIPTION
`section.
`
`2. Revise the DESCRIPTION section so that it is clear that the strengths of the tablets, i.e., 5 and
`10 mg, are in terms of the tofacitinib free-base. We recommend that you state the tofacitinib
`citrate equivalence in parentheses for added clarity.
`
`3. Revise the molecular formula in the DESCRIPTION section to a standard format, i.e., with
`subscripts for numeric designations.
`
`4. Revise the HOW SUPPLIED/STORAGE AND HANDLING section of the package insert to
`include a description of the imprinting of the tablets as per 21 CFR 201.57(c)(17)(iii).
`
`5. Revise the storage and handling statement to include the following reference “[see USP
`Controlled Room Temperature],” after the excursion temperature ranges.
`
`
`Reference ID: 3175247
`
`

`

`CMC Labeling Review/EES Status/Overall CMC Recommendation
`
`p. 2
`
`N203214
`
`
`Container and Carton Labels – Comments of 06-AUG-2012
`
`1. Revise the established name of the drug product to “tofacitinib tablets” while retaining the
`strength as 5 or 10 mg and include a footnote stating "each tablet contains 8 mg tofacitinib citrate
`equivalent to 5 mg tofacitinib,"
`
`
`
`
`2. Submit revised bottle and carton label mock-ups that indicate the placement of the expiration
`date and lot number of the drug product (as per 21 CFR 201.1).
`
` A
`
` revised package insert has been submitted to address the comments above, as well as revised
`container labels. As an example, the mock-up for the container label for the 10 mg strength with
`180 count presentation is reproduced below.
`________________________________________________________
`
`
`Evaluation: Adequate. In compliance with 21 CFR 201.57(c)(4)(ii), the applicant has revised
`the DOSAGE FORMS AND STRENGTHS section of the package insert to include descriptions
`of the identifying characteristics of the dosage form for each strength of the drug product (i.e.,
`color, shape, debossed information). The DESCRIPTION section is revised such that it is now
`clear that strengths are given in terms of the free base amount of drug (i.e., 5 and 10 mg), and the
`tofacitinib citrate equivalent amounts have been included in parentheses as suggested. Also in
`that section, the molecular formula has been corrected as requested. The HOW SUPPLIED/
`STORAGE AND HANDLING section now includes a description of the imprinting (debossing)
`of the tablets and the reference to USP Controlled Room Temperature is included following the
`recommendations for storage and handling.
`
`The applicant has submitted revised container labels to address the two comments above.
`Specifically, the established name has been revised so the strength and the name match and the
`footnote is included to indicate salt equivalency. Also the black area is space available for the
`expiry and lot number.
`
`
`Reference ID: 3175247
`
`(b) (4)
`
`(b) (4)
`
`

`

`CMC Labeling Review/EES Status/Overall CMC Recommendation
`
`p. 3
`
`
`
`
`
`
`
`
`
`_______________________________
`Craig M. Bertha, Ph.D.
`Chemist, ONDQA
`
`N203214
`
`
`Establishment Evaluation Request – Office of Compliance Recommendation Status
`The Office of Compliance has entered an “Acceptable” recommendation into the EES on 16-
`AUG-2012.
`
`Overall CMC Recommendation for NDA 203214
`The application is recommended to be approved.
`
`
`
`
`
`
`
`
`
`
`cc:
`
`ONDQA/DIV III/EDuffy
`OND/DPARP/NNikilov
`OCP/DCPII/LJain
`OND/DPARP/LLeshin
`OB/DBIII/YKim
`OND/DPARP/PBowen
`OPS/OMPT/DHenry
`ONDQA/Biopharm/JDuan
`ONDQA/DNDQA3/ASchroeder
`ONDQA/DNDQA3/CBertha/8/16/2012
`ONDQA/DNDQA3/YWang
`ONDQA/DNDQA2/BKurtyka
`ONDQA/DNDQA3/PPeri
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3175247
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CRAIG M BERTHA
`08/16/2012
`
`PRASAD PERI
`08/16/2012
`I concur
`
`Reference ID: 3175247
`
`

`

`
`
`DATE:
`
`TO:
`
`FROM:
`
`
`
`02-AUG-2012
`
`N203214 File
`
`Craig M. Bertha, Ph.D.
`Chemistry Reviewer
`ONDQA, Division III, Branch VIII
`
`
`
`MEMORANDUM: DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC
`HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`THROUGH: Prasad S. Peri, Ph.D.
`
`
`Branch Chief
`
`
`ONDQA, Division III, Branch VIII
`
`SUBJECT: CMC review of labels and labeling for NDA 203214
`
`SUMMARY:
`Package Insert
`The DOSAGE FORMS AND STRENGTHS section currently provides a reference to the
`DESCRIPTION section for the information complying with 21 CFR 201.57(c)(4)(ii). The
`presentation of the strength in terms of the tofacitinib free base is not clear in the
`DESCRIPTION section. The molecular formula should be modified to a standard format (with
`subscript numerical designations). The HOW SUPPLIED/STORAGE AND HANDLING
`section does not include a description of the tablet imprinting as per 21 CFR 201.57(c)(17)(iii).
`The storage and handling statement should be modified to include “[see USP Controlled Room
`Temperature]” to be consistent with recommended practice.
`
`Deficiency: Revise the DOSAGE FORMS AND STRENGTHS section of the package insert to
`include the information required by 21 CFR 201.57(c)(4)(ii), rather than referencing the
`DESCRIPTION section.
`
`Deficiency: Revise the DESCRIPTION section so that it is clear that the strengths of the tablets,
`i.e., 5 and 10 mg, are in terms of the tofacitinib free-base. It is recommended that you state the
`tofacitinib citrate equivalence in parentheses for added clarity.
`
`Deficiency: Revise the molecular formula in the DESCRIPTION section to a standard format,
`i.e., with subscripts for numeric designations.
`
`Deficiency: Revise the HOW SUPPLIED/STORAGE AND HANDLING section of the package
`insert to include a description of the imprinting of the tablets as per 21 CFR 201.57(c)(17)(iii).
`
`Deficiency: Revise the storage and handling statement to include the following reference “[see
`USP Controlled Room Temperature],” after the excursion temperature ranges.
`
`
`Reference ID: 3168516
`
`

`

`N203214
`
`CMC Labeling Review
`
`p. 2
`
`Carton and Container Labels
`
`The product of both strengths is to be packaged in 180 and 60 count HDPE bottles with
`induction seal liners. The application provides carton and container labels for each bottle
`presentation (2 strengths in 2 bottle presentations).
`
`(b)(4)® (tofacitinib citrate)
`The most current labels have the name for the drug product as
`Tablets and the strength as 5 or 10 mg. However, there is an asterisk after the 5 or 10 mg
`strength that states that “*Each tablet contains tofacitinib citrate equivalent to 5 mg tofacitinib”
`and “*Each tablet contains tofacitinib citrate equivalent to 10 mg tofacitinib.” Therefore, the
`strength and the established name do not match as crurently proposed. The established name
`being used for the product is tofacitinib citrate. However, the strength is provided in terms of the
`free base. To be consistent with the policy promoted by the USP and the Agency to not include
`the salt forms in the established names of drug products, the “citrate” should be removed from
`the established name and a footnote added onto the label stating that the actual form of the drug
`substance is the citrate salt as well as the strength of 8 or
`(we) in terms of that form.
`
`Deficiency: Revise the established name ofthe drugproduct to "tofacitinib tablets " while
`retaining the strength as 5 or 10 mg and include afootnote stating "each tablet contains 8 mg
`tofacitinib citrate equivalent to 5 mg tofacitinib, ’
`M"
`
`None of the bottle or carton label mock-ups would appear to include any indication of where the
`expiration date or the lot number would be located (21 CFR 201.17, 201.18, and 201.100(b)(6)).
`The labels only list Pfizer as the distributor, but this is in compliance with 21 CFR 201.1(h)(5).
`Because the dosage and administration instructions in the package insert are relatively extensive,
`the DOSAGE AND USE instructions on the bottle labels and cartons merely state that the
`patient or practitioner is to see the accompanying prescribing information. That approach is
`consistent with 21 CFR 201.55. The bottle labels and cartons state that the product should not be
`repackaged, thus, this complies with the requirements of 21 CFR 201.100(b)(7). Other
`information included appears to be consistent with labeling regulations.
`
`Deficiency: Provide revised bottle and carton label mock-ups that indicate the placement ofthe
`expiration date and lot nmnber ofthe drugproduct (as per 21 CFR 201.] 7, 201.18,
`200.100(b)(6)).
`
`DMEPA Labeling Review and Comments
`The DMEPA has provided a consult review for the labeling date 12—JUN-2012,
`
`(law)
`
`The only container closure systems currently proposed are the 60 and 180
`count HDPE bottles with foil induction lidding, for both strengths. With regard to the DMEPA
`comments for the applicant, comment B] should be revised to account for the discrepancy
`between the established name and the product strengths, as discussed above. Therefore, the
`DMEPA comments could be revised as such:
`
`B. Container Labels
`
`1. The established name includes the active ingredient and the finished dosage form.
`Relocate the dosage form, ‘tablets’, to appear after (Tofacitinib). For example:
`
`Reference ID: 3168516
`
`

`

`N203214
`
`CMC Labeling Review
`
`p. 3
`
`Tradename
`
`(Tofacitinib)
`Tablets
`
`10 mg
`
`Remove DMEPA comment D as
`
`09(4)
`
`RECOMNIENDATION: The following labeling connnents are to be forwarded to the
`applicant. Also, refer to the suggested revisions for the DMEPA labeling recommendations
`immediately above.
`
`Draft CMC Labeling Comments
`
`1. The following comments pertain to the package insert.
`
`a. Revise the DOSAGE FORMS AND STRENGTHS section of the package insert
`to include the information required by 21 CFR 201 .57(c)(4)(ii), rather than
`referencing the DESCRIPTION section.
`
`b. Revise the DESCRIPTION section so that it is clear that the strengths of the
`tablets, i.e., 5 and 10 mg, are in terms of the tofacitinib free—base. It is
`recommended that you state the tofacitinib citrate equivalence in parentheses for
`added clarity.
`
`c. Revise the molecular formula in the DESCRIPTION section to a standard format,
`i.e., with subscripts for nlnneric designations.
`
`d. Revise the HOW SUPPLIED/STORAGE AND HANDLING section of the
`
`package insert to include a description of the imprinting of the tablets as per 21
`CFR 201.57(c)(l7)(iii).
`
`e. Revise the storage and handling statement to include the following reference
`“[see USP Controlled Room Temperature],” after the excursion temperature
`ranges.
`
`2. The following comments pertain to the container and carton labels.
`
`a. Revise the established name of the drug product to “tofacitinib tablets” while
`retaining the strength as 5 or 10 mg and include a footnote stating "each tablet
`contains 8 mg tofacitinib citrate equivalent to 5 mg tofacitinib,"
`M”
`
`b. Provide revised bottle and carton label mock—ups that indicate the placement of
`the expiration date and lot number of the drug product (as per 21 CFR 201.1,
`201.18, 200.100(b)(6)).
`
`Reference ID: 3168516
`
`

`

`CMC Labeling Review
`
`p. 4
`
`
`
`
`
`
`
`
`
`
`
`
`
`_______________________________
`Craig M. Bertha, Ph.D.
`CMC Reviewer, ONDQA
`
`
`
`
`
`N203214
`
`
`
`
`
`
`
`
`
`
`
`
`cc:
`
`ONDQA/DIV III/EDuffy
`OND/DPARP/NNikilov
`OCP/DCPII/LJain
`OND/DPARP/LLeshin
`OB/DBIII/YKim
`OND/DPARP/PBowen
`OPS/OMPT/DHenry
`ONDQA/Biopharm/JDuan
`ONDQA/DNDQA3/ASchroeder
`ONDQA/DNDQA3/CBertha/8/2/2012
`ONDQA/DNDQA3/YWang
`ONDQA/DNDQA2/BKurtyka
`ONDQA/DNDQA3/PPeri
`
`
`
`
`
`
`Reference ID: 3168516
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`CRAIG M BERTHA
`08/02/2012
`
`PRASAD PERI
`08/02/2012
`I concur
`
`Reference ID: 3168516
`
`

`

`23-Jul-2012
`
`Bogdan Kurtyka, Ph.D.
`CMC Reviewer
`
`Prasad Peri, Ph.D.
`Chief, Branch VIII ONDQA Division III
`Eric Duffy
`Director, ONDQA Division III
`
`
`
`CMC Review #1 for NDA 203-214
`
`Ying Wang, Ph.D.
`Craig Bertha, Ph.D.
`
`Update of NIR methods
`
`
`
`
`
`
`
`Memorandum
`
`Department of Health and Human Serviced
`Food and Drug Administration
`Center for Drug Evaluation and Research
`
`
`Date:
`
`From:
`
`
`
`Through:
`
`
`
`
`
`
`
`To:
`
`
`CC:
`
`
`
`
`Subject:
`
`Inspection team members participating in inspection of drug product manufacturing plant reported that
`NIR methods were updated following a major repair of NIR analyzer after CMC Review #1 that
`recommended approval of NIR methods was finalized. The details of the update were submitted to the
`application on 20-Jul-2012. See “Attachment” for detailed information.
`
`Recommendation:
`
`The submitted information demonstrates that updated NIR methods are adequate.
`
`
`
`Reference ID: 3162729
`
`Page 1 of 3
`
`2 Pages Have Been Withheld In Full As b4 (CCI/TS) Immediately Following This Page
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`BOGDAN KURTYKA
`07/23/2012
`
`PRASAD PERI
`07/24/2012
`
`ERIC P DUFFY
`07/24/2012
`
`Reference ID: 3162729
`
`

`

`(b) (4)
`
`® (tofacitinib) Tablets, 5 &10 mg
`NDA 203214
`
`Chemistry, Manufacturing, and Controls
`Division Director’s Summary Basis of Action
`
`Applicant:
`
`Pfizer Inc.
`445 Eastern Point Road
`
`Groton, CT 06340
`
`For the treatment of adult patients with moderately to severely active rheumatoid
`Indication:
`arthritis who have had an inadequate response to one or more disease—modifying anti-rheumatic
`drugs. The recommended starting dose of the drug is 5 mg two times a day taking orally and
`may increase to 10 mg two times a day for some patients.
`
`Presentation:
`
`(b)(4)® Tablets are packaged in 60 and 180 count HDPE bottles.
`
`EER Status: Recommendations:
`Consults:
`EA —
`CDRH—
`
`Pending as of July 2, 2012.
`Categorical exclusion provided
`N/A
`
`Statistics —
`
`N/A
`
`Methods Validation —
`
`See assessment by John Kauffman of St. Louis Lab on the
`(mo and
`(mo
`
`DMETS-
`Biopharm—
`Microbiology —
`Pharm/toxicology —
`
`Acceptable
`Acceptable
`Acceptable
`Acceptable
`
`Background: This drug development has progressed since late 2004 when Pfizer submitted their
`1ND for rheumatoid arthritis. Note this same active has been studied for multiple indications
`such as irnmunosuppressive agent for development in human transplantation
`a”)
`(m4)
`treatment of Crohn’s disease
`(mo for treatment of chronic plaque psoriasis
`(5);)“ for treatment ofulcerative colitis
`(m4) and for treatment 0fdry eye
`
`The drug substance and drug product are developed using a Quality by Design (QbD) Strategy
`for better assurance of quality from a manufactiuer and patient perspective. A CMC only EOP2
`meeting was held with Pfizer on March 7, 2011 where several aspects of the control strategy for
`Identity, Assay (potency), Real Time Release Testing, Content Uniformity, and Disintegration
`were discussed.
`
`The CMC part of the NDA is in a pilot program with parallel reviews between FDA and
`European Medicinal Agency OSMA). There have been extensive discussions between the two
`agencies on major CMC issues particularly in Quality by Design (QbD) areas. Some of the
`comments and approaches were harmonized between the two agencies. Due to the differences in
`
`Reference ID: 31 54370
`
`

`

`regulations and precedents some of the comments and approaches have not been harmonized.
`
`Drug Substance:
`The drug substance tofacitinib citrate (CP-690,550-10) is a white to off—white crystalline
`(”mthat is
`on»
`
`and it is non hygroscopic. Tofacitinib citrate is highly soluble
`as per the Biopharmaceutics Classification System and the applicant indicates that it has
`low permeability 03CS class 3). The structure of tofacitinib citrate includes an arylamine
`fimction, which is a structural alert for potential mutagenicity. The firm performed a
`series of genetox tests which were negative, as well as QSAR analysis which was also
`negative. Note that the impurities also have the same structural alert for mutagenicity,
`and are therefore by extension negative for mutagenicity. The drug substance is not
`photosensitive and the stability data provided supports both the proposed retest period of
`(mo, as well as the post-approval stability protocol proposed.
`
`H3C/Il/In
`
`.//_z\
`
`12/
`
`tofacitinib citrate
`
`3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-
`yl)amin0)piperidin— l -yl)-3-oxopropanenitrile, 2-hydroxypr0pane- l ,2,3-t1icarboxylic acid
`
`Molecular Formula: C16H20N50-C6H307 (citrate salt)
`Molecular Weight:
`504.50 g/mol (312.37 g/mole for free base)
`
`The applicant has also followed Quality by Design (QbD) principles in their development
`of the manufacturing process for the drug substance and the method that will be used for
`the determination of drug substance assay and impurities. These approaches included the
`use of risk-based assessment to identify drug substance quality attributes and process
`parameters that had potential to impact drug product safety and efficacy. Critical quality
`attributes (CQAs) of the drug substance were identified and process parameters were
`categorized as critical or non—critical (CPPs or NCPPs). The applicant performed
`multivariate experiments and modeled output data to establish links between synthesis
`process parameters and the quality attributes of intermediates and the final drug
`substance. In this way they defined the acceptance criteria for the material attributes of
`the synthesis materials (starting materials, reagents, etc.) and “operational boundaries”
`for process parameters, optimizing the process and providing greater assurance of the
`
`Reference ID: 31 54370
`
`

`

`production of acceptable drug substance. In conjunction with these studies the applicant
`gained an understanding of the fate of, and process parameters that afi'ected the synthetic
`impurities in the drug substance. Overall, flie applicant has presented additional
`information and data demonstra '
`enhanced
`ocess understandin of the
`
`substance
`
`thesis
`
`ocess
`
`using QbD approaches for analytical methods and is not taking any regulatory action with
`respect to the proposed-, which has been acknowledged by Pfizer.
`
`The final drug substance specifications include the following parameters: Description,
`Identity (IR, LC), Particle Size, Assay, Comter Ion, Impurities, Residue on Ignition,
`Heavy Metals, Residual Solvents, and Water Content.
`
`Drug substance retest period is-.
`
`
`
`The drug substance is manufactured at Pfizer Ireland Pharmaceuticals, Ringaski
`Ireland GMPs acc
`table based
`rofile . The dru substance is
`
`
`cka ed in
`
`
`Drug Substance: Satisfactory
`
`Drug Product:
`Tofacitinib Citrate is formulated as film—coated round immediate release tablets available
`
`in two strengths, 5 mg and 10 mg (based on the equivalent am01mt of Tofacitinib base).
`The 5 mg tablets are white to off-white, film-coated, round tablets debossed wifli “Pfizer”
`on one side and “JKI ” on the other side.
`
`
`
`
`Risk assessment and quality by
`or ormulation and manufacturing process
`
`development.
`, tablet content uniformity is
`defined as a critical quality attribute (CQA) and drug substance particle size is defined as
`a critical quality attribute (CQA). The acceptance criteria for the drug substance particle
`size distribution have been discussed extensively during the review cycle and were found
`acceptable. Comprehensive pharmaceutical development information is provided in the
`submission. Design space for the process parameters has been established through risk
`
`Reference ID: 31 54370
`
`

`

`assessment, design of experiments, prior knowledge and modeling.
`
`Real time release tests of identification, assay and dosage content uniformity by NIR
`have been proposed for the drug product. This is a relatively novel approach and has
`only been used in a few recently approved products. Comprehensive model development
`and validation information (for the proposed analytical methods) have been submitted in
`the application which were reviewed in depth. The methods have been deemed adequate
`for their intended purposes. In conjunction with the NIR method, a large sample size and
`its associated acceptance criteria have been proposed for the dose content uniformity test
`at release. The same acceptance criteria have been accepted for other drug products. The
`proposed acceptance criteria for dose content uniformity using the large 11 sample size
`have been deemed acceptable at this point.
`
`The final drug product specifications include the following parameters: Appearance,
`Identity (NIR or UV, LC), Assay (NIR or LC at release and HPLC on stability),
`Uniformity of Dosage Units (NIR or LC at release and HPLC on stability), Individual
`Specified Degradation Products, Individual Unspecified Degradation Products, Total
`Degradation Products, Disintegration,
`W". Note that the disintegration
`specification was negotiated
`(m4)
`
`The drug product is packed in high-density polyethylene a-IDPE) bottles with desiccant
`and closures with induction seal liners.
`(km)
`
`The Drug Product is manufactured and packaged in Frieburg, Germany and is also being
`packaged in Puerto Rico. On the PAI inspection of the Frieburg facility it was noted that
`a change was made to the NIR calibration model following instrumentation malfunction.
`The change is considered potentially significant. Pfizer will be asked for information
`supporting the adequacy of the revised model, with re—validation. Review will be the
`subject of an addendum to the CMC review.
`
`The submitted drug product stability data include 12 months at the long term storage condition
`of25°C/60%RH and 6 month at the accelerated storage condition of40°C/75%RH for 3 batches
`ofeach strength. The stability data support the proposed 24 month shelf life for the drug product
`when stored at the proposed 20°C to 25°C (68°F to 77°F), with excursions permitted between
`15°C and 30°C (between 59°F and 86°F).
`
`Drug Product: Satisfactory.
`
`Overall Conclusion:
`
`From a CMC perspective, the application is recommended for approval pending an
`acceptable recommendation from the Office of Compliance. Finalized labels are not yet
`
`provided and hence not included in this review.
`
`Reference ID: 31 54370
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`ERIC P DUFFY
`07/03/2012
`
`Reference ID: 3154370
`
`

`

`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`
`
`NDA 203214
`
`® (tofacitinib) Tablets, 5 &10 mg
`
`Pfizer Inc.
`
`
`
`
`Craig M. Bertha, Ph.D.
`Donghao (Robert) Lu, Ph.D.
`Ying Wang, Ph.D.
`Bogdan Kurtyka, Ph.D.
`
`
`ONDQA/DNDQA III/Branch VIII, DNDQA II/Branch IV,
`and DNDQA I/Branch I
`for
`Division of Pulmonary, Allergy, and Rheumatology Products
`
`
`
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`Reference ID: 3151040
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`(b) (4)
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`Table of Contents
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`Table of Contents .....................................................................................................2
`
`Chemistry Review Data Sheet.................................................................................4
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`The Executive Summary .........................................................................................8
`
`1. Recommendations ...................................................................................................................... 8
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`A. Recommendation and Conclusion on Approvability ....................................................................... 8
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`B. Recommendation on Phase 4 (Post-Marketing) Commitments. Agreements. and/or Risk
`Management Steps. if Approvable ................................................................................................... 8
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`II. Summary of Chemistry Assessments......................................................................................... 8
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`A. Description of the Drug Product(s) and Drug Substance(s) ............................................................. 8
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`III. Administrative ......................................................................................................................... 11
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`A. Reviewer’s Signature ...................................................................................................................... 11
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`B. Endorsement Block ......................................................................................................................... 11
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`C. CC Block........................................................................................................................................ 11
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`Chemistry Assessment ........................................................................................... 12
`
`Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2:
`I.
`Body Of Data .......................................................................................................... 12
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`S DRUG SUBSTANCE [tofacitinib citrate, Pfizer] ...................................................................... 12
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`5.1 General Information [tofacitinib citrate, Pfizer] ............................................................................. 12
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`82 Manufacture [tofacitinib citrate, Pfizer] ......................................................................................... 15
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`8.3 Characterization [tofacitinib citrate. Pfizer] ................................................................................... 58
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`8.4 Control of Drug Substance [tofacitinib citrate. Pfizer] .................................................................. 62
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`8.5 Reference Standards or Materials [tofacitinib citrate, Pfizer] ........................................................ 80
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`8.6 Container Closure System [tofacitinib citrate, Pfizer] ................................................................... 82
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`8.7 Stability [tofacitinib citrate. Pfizer] ................................................................................................ 82
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`P DRUG PRODUCT [tofacitinib tablets] .................................................................................... 122
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`R] Description and Composition of the Drug Product [tofacitinib tablets] ....................................... 122
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`P2 Pharmaceutical Development [tofacitinib tablets] ....................................................................... 125
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`Reference ID: 3151040
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`Page 2
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`'TE'X
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`CHEMISTRY REVIEW
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`f'fe"
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`P.3 Manufacture [tofacitinib tablets] .................................................................................................. 179
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`P4 Control of Excipients [tofacitinib tablets] .................................................................................... 188
`
`P5 Control of Drug Product [tofacitinib tablets] ............................................................................... 190
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`R6 Reference Standards or Materials [tofacitinib tablets] ................................................................. 230
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`R7 Container Closure System [tofacitinib tablets] ............................................................................ 230
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`R8 Stability [tofacitinib tablets] ......................................................................................................... 232
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`A APPENDICES .........................................................................................................................280
`
`Al Facilities and Equipment (biotech only) ...................................................................................... 280
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`A2 Adventitious Agents Safety Evaluation ....................................................................................... 280
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`A3 Novel Excipients ......................................................................................................................... 281
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`R REGIONAL INFORMATION ................................................................................................281
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`R1 Executed Batch Records ............................................................................................................... 281
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`R2 Comparability Protocols ............................................................................................................... 281
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`R3 Methods Validation Package ........................................................................................................ 281
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`II. Review Of Common Technical Document-Quality (Ctd—Q) Module 1 ..................................281
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`A. Labeling & Package Insert ........................................................................................................... 281
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`B. Environmental Assessment Or Claim Of Categorical Exclusion .................................................. 281
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`Reference ID: 3151040
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`Page 3
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`Chemistry Review Data Sheet
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`Chemistry Review Data Sheet
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`1. NDA 203214
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`2. REVIEW #: l
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`3. REVIEW DATE: 26-JUN-2012
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`4. REVIEWERS: Craig M. Bertha, Ph-D. (drug substance)
`Donghao (Robert) Lu, Ph.D. (
`(W) for drug substance
`impurities method)
`Ying Wang, Ph.D. (drug product)
`Bogdan Kurtyka, PhD. (near infrared methodology)
`
`5. PREVIOUS DOCUMENTS:
`
`Previous Documents
`N/A
`
`Document Date
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`6. SUBMISSION(S) BEING REVIEWED:
`
`Submissiong 5) Reviewed
`Original
`Amendment
`Amendment
`Amendment
`
`Document Date
`21-OCT—201 l (assigned 31-0CT—201 1)
`13—JAN-2012 (response to 74-day letter)
`30—APR—20 12 (response to 16-MAR—20 l 2 information request)
`1 1-JUN-2012 (response to 1-JUN-2012 information request)
`
`7. NAME & ADDRESS OF APPLICANT:
`
`Name:
`
`Pfizer Inc.
`
`Address:
`
`445 Eastern Point Road
`Groton. CT 06340
`
`Representative:
`
`Nickie V. Kilgore. DVM. Director Worldwide Regulatory
`Strategy
`
`Telephone:
`
`(860)-441-5030
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`Reference ID: 3151040
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`Page 4
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`Chemistry Review Data Sheet
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`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`(5)(4)® (proposed)
`a) Proprietary Name:
`b) Non-Proprietary Name (USAN): tofacitinib citrate
`c) Code Name/# (0NDQA only): CP—690.550-10
`d) Chem. Type/Submission Priority (0NDQA only):
`
`0 Chem. Type: 1
`
`0 Submission Priority: S
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1)
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`10. PHARMACOL. CATEGORY: Janus—associated kinase (JAK) inhibitor for
`treatment of rheumatoid arthritis
`
`11. DOSAGE FORM:
`
`tablets
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`12. STRENGTH/POTENCY: 5 & 10 mg tofacitinib (8 &
`citrate, respectively)/tablet; taken BID
`
`(b) (4)
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`tofacitinib
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`13. ROUTE OF ADMINISTRATION: oral
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`l4. Rx/OTC DISPENSED:
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`X Rx
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`OTC
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`15. SPOTS {SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
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`SPOTS product — Form Completed
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`X Not a SPOTS product
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`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
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`FORMULA, MOLECULAR WEIGHT:
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`3-((3R,4R)-4-methyl-3-(methyl(7H-pyrrolo[2,3-d]pyrimidin-4-
`yl)amino)piperidin— l —yl)—3-oxopropanenit1ile, 2—hydroxypropane— 1 ,2,3—tricar