`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`
`APPLICATION NUMBER:
`021825Orig1s000
`
`CHEMISTRY REVIEW(S)
`
`
`
`
`
`
`

`

`
`
`ONDQA Division Director’s Memo
`NDA 21825, FERRIPROX (deferiprone) tablets, 500 mg
`Date: 12-OCT-2011
`
`Introduction
`FERRIPROX (deferiprone) tablets are immediate-release, film-coated tablets supplied in one
`strength (500 mg). FERRIPROX is indicated for the treatment of patients with excessive body
`iron stores due to chronic transfusion therapy. The dose is 25-33 mg/kg body weight, taken orally
`three times daily for a total dose of 75-
` mg/kg body weight. The maximum safe dose is
`
`mg/kg body weight/day.
`
`ONDQA recommends approval of this NDA. There are no outstanding CMC deficiencies for
`this NDA.
`
`Administrative
`The current submission is a Class 2 Resubmission to the Agency’s 30-NOV-2009 Complete
`Response action. The Chemistry, Manufacturing and Controls assessment for the current cycle is
`captured in Chemistry Review #3 (dated 26-SEP-2011), the ONDQA Biopharmaceutics Review
`(dated 16-SEP-2011), and the ONDQA Biopharmaceutics Memorandum (25-SEP-2011).
`Primary CMC review of drug substance and drug product information, as well as
`biopharmaceutics information, confirm an approval recommendation, and all primary reviews
`confirm that there are no outstanding CMC deficiencies.
`
`At the time of primary review completion, an overall recommendation from the Office of
`Compliance was still pending. An overall acceptable recommendation was issued by the Office
`of Compliance on 07-OCT-2011. This pending issue is now resolved.
`
`This NDA is recommended for approval from a Chemistry, Manufacturing and Controls
`standpoint.
`
`Insert the following language into the approval letter: “Based on the stability data provided
`in your application, the drug product is granted a 24-month expiry when stored at USP
`controlled room temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-
`86ºF).”
`
`
`Drug Substance (Deferiprone)
`Chemical Name: 1,2-dimethyl-3-hydroxypyrid-4-one
`
`
`
`
`
`
`
`
`
`
`
`
`
`Reference ID: 3028056
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`Deferiprone is a new chemical entity. Deferiprone is a bidentate iron chelator that preferentially
`binds ferric ions into a 3:1 (deferiprone: iron) complex at low pH. Bulk drug substance is a white
`to pink crystalline powder.
`
` Deferiprone is highly soluble in water at pH 1-7.5 and has high
`permeability, thus is a BCS class 1 drug. Structural elucidation studies show the material is
`prepared
`
`.
`
`
`Manufacture is by a
`
`
`
`
`
`
`. Manufacture and control of bulk process at each proposed site is described in
`Apotex, Inc.’s type II DM 10867. During the CMC review, the DMF was reviewed and was
`found adequate to support approval of this application.
`
`The CMC review grants a re-test period of
`
` for the Apotex Pharmachem and
` for the
` site when stored
` sites, and a retest period of
`under controlled room temperature. This is in agreement with what the Applicant proposes, and
`not additional action is needed.
`
`
`Drug Product (Deferiprone Tablets, 500 mg)
`
`The drug product is a scored tablet manufactured
`. All excipients used in the formulation are compendial and are conventional for solid oral
`dosage forms. The release specification includes testing for identity, average tablet weight,
`dissolution, content uniformity/assay, and degradants (unspecified and total). The CMC review
`confirms that the tests are adequate to establish identify, purity and strength of the drug product.
`The methods for assay and related substances were revised after NDA submission. Descriptions
`of the analytical methods are complete and provided in sufficient detail. Representative spectra
`and chromatograms have been provided. Validation studies for the non-compendial methods are
`complete and establish the methods as adequate for the intended use.
`
`The proposed commercial presentation is 100 tablets in a 120cc round, white HDPE bottle.
`There is no carton for the bottle. Suppliers and materials of construction for each packaging
`component are identified and an acceptance specification for each component is provided. All
`Type III DMFs for the component suppliers and their materials of construction were evaluated as
`acceptable to support this NDA.
`
`
`The CMC review grants a 24-month expiration dating period when stored at USP controlled room
`temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF).
`
`Insert the following language into the approval letter:
`“Based on the stability data provided in your application, the drug product is granted a 24-
`month expiry when stored at USP controlled room temperature 20-25ºC (68-77ºF);
`excursions permitted to 15-30ºC (59-86ºF).”
`
`
`
`Reference ID: 3028056
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`---------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
`---------------------------------------------------------------------------------------------------------
`/s/
`----------------------------------------------------
`
`RICHARD T LOSTRITTO
`10/12/2011
`
`Reference ID: 3028056
`
`

`

`
`
`
`
`
`
`
`
`
`
`
`CMC REVIEW
`
`NDA 21-825
`
`
`Ferriprox®
`
`
`ApoPharma, Inc.
`
`
`
`William M. Adams
`Review Branch I
`Division of New Drug Quality Assessment I
`Office of New Drug Quality Assessment
`
`For the Division of Hematology Products
`
`
`
`
`
`
`
`
`
`Reference ID: 3020615
`
`

`

`
`
`
`
`CMC REVIEW OF NDA 201532
`
`
`
`Table of Contents
`
`
`Table of Contents .....................................................................................................2
`
`CMC Review Data Sheet .........................................................................................4
`
`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 CMC 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.................................................. 12
`C. Basis for Approvability or Not-Approval Recommendation ................................................... 12
`III. Administrative ......................................................................................................................12
`CMC Assessment....................................................................................................13
`
`I. Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2: Body Of Data13
`S API................................................................................................................................................. 13
`S.1
`General Information.....................................................................................................................13
`S.2
`Manufacture ..................................................................................................................................13
`S.3
`Characterization............................................................................................................................14
`S.4
`Control of API...............................................................................................................................14
`S.5
`Reference Standards or Materials...............................................................................................38
`S.6
`Container Closure System............................................................................................................38
`S.7
`Stability..........................................................................................................................................38
`P Drug Product................................................................................................................................ 39
`P.1
`Description and Composition of the Drug Product....................................................................39
`P.2
`Pharmaceutical Development ......................................................................................................39
`P.3
`Manufacture ..................................................................................................................................39
`P.4
`Control of Excipients ....................................................................................................................40
`P.5
`Control of Drug Product ..............................................................................................................40
`P.6
`Reference Standards or Materials...............................................................................................52
`P.7
`Container Closure System............................................................................................................52
`P.8
`Stability..........................................................................................................................................52
` APPENDICES............................................................................................................................. 56
`A.1
`Facilities and Equipment (biotech only)......................................................................................56
`A.2
`Adventitious Agents Safety Evaluation.......................................................................................56
`A.3
`Novel Excipients............................................................................................................................56
`R REGIONAL INFORMATION.................................................................................................. 56
`
`A
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`CMC Review #1
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`Page 2 of 62
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`CMC REVIEW OF NDA 201532
`
`
`
`R1 Executed Batch Records....................................................................................................................56
`R2 Comparability Protocols ...................................................................................................................56
`R3 Methods Validation Package ............................................................................................................56
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1.............................56
`A. Labeling & Package Insert.......................................................................................................... 56
`B. Environmental Assessment Or Claim Of Categorical Exclusion ............................................ 58
`III. List Of Deficiencies to be Communicated............................................................................58
`
`
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`CMC Review #1
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`Page 3 of 62
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`Reference ID: 3020615
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`

`

`
`
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`
`
`CMC REVIEW OF NDA 21-825
`CMC Review Data Sheet
`
`CMC Review Data Sheet
`
`NDA 21-825
`
`REVIEW 03
`
`REVIEW DATE: 26 Sep 2011
`
`REVIEWER: William Adams
`
`PREVIOUS DOCUMENTS:
`
`Document
`Amendment N-002 (CMC RU, tablets & solution)
`CMC IQA
`Amendment (EA submission; not in Darrts or EDR)
`Amendment N-004 (resubmission of CMC RU, tablets & solution)
`Amendment N-006 (CMC RU, tablets)
`IR letter (CMC only)
`CMC Review 01
`Amendment N-008 (partial response to IR)
`DR Letter (CMC)
`Amendment N-009 (intent to respond to DR letter)
`Amendment N-010 (non-CMC & labeling)
`Amendment N-012 (complete CMC response to IR letter)
`Amendment N-013 (complete CMC response to DR letter)
`Amendment N-015 (new NDA; clinical and labeling)
`Amendment N-016 (draft labels & labeling)
`Amendment N-017 (request trade name review)
`Amendment N-020 (CMC information; not in EDR)
`Correspondence (denial of trade name)
`74-Day Letter (multi-discipline)
`Amendment N-021 (response to 74-day letter; not in EDR)
`Amendment N-024 (request for trade name reconsideration)
`Amendment N-026 (biostat & labeling)
`Amendment N-028 (minor CMC revisions)
`Correspondence (proprietary name granted)
`CMC Review 02
`Complete Response letter (clinical, clinpharm, CMC, labeling, EES)
`General Advice (labeling comments)
`
`SUBMISSION(S) BEING REVIEWED:
`
`Document
`Amendment N-058 (partial response - CMC & draft labeling)*
`Amendment N-059 (complete response; class 2 resubmission)
`Amendment N-060 (draft trade name & package insert)
`IR letter (labeling)
`
`Darrts Submit Date
`12 Mar 2007
`27 Mar 2007
`30 Aug 2007
`26 Sep 2007
`21 Dec 2007
`28 Feb 2008
`21 Mar 2008
`27 Mar 2008
`27 Mar 2008
`12 Jun 2008
`27 Jun 2008
`29 Sep 2008
`30 Oct 2008
`29 Jan 2009
`17 Feb 2009
`25 Feb 2009
`18 Mar 2009
`24 Mar 2009
`31 Mar 2009
`07 May 2009
`15 Jun 2009
`09 Jul 2009
`06 Aug 2009
`11 Sep 2009
`20 Oct 2009
`30 Nov 2009
`02 Dec 2009
`
`Darrts Submit Date
`25 Feb 2011
`14 Apr 2011
`29 Apr 2011
`03 Jun 2011
`
`
`
`1.
`
`2.
`
`3.
`
`4.
`
`5.
`
`
`
`6.
`
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`CMC Review #1
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`Reference ID: 3020615
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`

`

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`CMC REVIEW OF NDA 21-825
`CMC Review Data Sheet
`
`
`07 Jun 2011
`Amendment N-063 (draft container labels)
`14 Jun 2011
`Amendment N-064 (draft container labels)
`16 Jun 2011
`IR letter (CMC only)
`27 Jul 2011
`Amendment N-068 (proprietary name)
`28 Jul 2011
`Correspondence (proprietary name granted)
`10 Aug 2011
`IR Letter (CMC only)
`06 Sep 2011
`Amendment N-075 (clinical & labeling)
`19 Sep 2011
`IR Letter (CMC only)
`19 Sep 2011
`Email Partial Response to 09/19/11 IR Letter
`21 Sep 2011
`Minutes for 09/20/11 Tcon (not yet entered into Darrts)
`22 Sep 2011
`Email Complete Response to 09/19/11 IR Letter
`22 Sep 2011
`Amendment N-077 (multidiscipline response to multiple IR letters)
`23 Sep 2011
`Email Response to Biopharm Comment**
`26 Sep 2011
`Amendment N-078 (revised release/stability specification)
`* Response to General Advice letter dated 02 Dec 2009 (labeling) and partial response (CMC Questions 1-15) to
`Complete Response letter dated 30 Nov 2009
`** After discussion between Biopharm and the applicant, the Dissolution criterion was finalized in the 09/23/11
`Amendment.
`
`NAME & ADDRESS OF APPLICANT:
`
`Name:
`Address:
`
`Representative:
`
`Telephone:
`
`ApoPharma, Inc.
`200 Barmac Drive
`Toronto, Ontario, Canada M9L 2Z7
`Ms Lynda Sutton, Chief Regulatory Officer
`Cato Research Ltd.
`4364 south Alston Avenue
`Durham, NC 27713-2220
`919-361-2286
`
`Drug Product NAME/CODE/TYPE:
`
`
`7.
`
`
`
`8.
`
`
`a) Proprietary Name: Ferriprox®
`b) Non-Proprietary Name (USAN): Deferiprone
`c) Code Name/# (ONDQA only): L1, CP20, APO-66, PL1, DN-180-01-AF
`d) Chem. Type/Submission Priority (ONDQA only): 1S
`
`LEGAL BASIS FOR SUBMISSION: 505(b)(1)
`
`PHARMACOLOGICAL CATEGORY: Metal Chelator
`
`DOSAGE FORM: Immediate Release, Film-Coated Tablet
`
`STRENGTH/POTENCY: 500 mg
`
`ROUTE OF ADMINISTRATION: Oral
`
`Rx/OTC DISPENSED: Rx
`
`SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
`
`
`9.
`
`10.
`
`11.
`
`12.
`
`13.
`
`14.
`
`15.
`
`CMC Review #1
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`Page 5 of 62
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`Reference ID: 3020615
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`

`

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`CMC REVIEW OF NDA 21-825
`CMC Review Data Sheet
`
` SPOTS product – Form Completed
`
` √ Not a SPOTS product
`
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR FORMULA,
`MOLECULAR WEIGHT:
`
`
`Chemical Name
`Molecular Formula
`Molecular Weight
`Molecular Structure
`
`1,2-dimethyl-3-hydroxypyrid-4-one
`C7H9NO2
`139.15
`
`
`
`
`
`
`
`
`17.
`
`
`
`DMF # TYP
`E
`
`RELATED/SUPPORTING DOCUMENTS:
`
`A.
`
`Supporting DMFs:
`
`HOLDER
`
`ITEM
`REFERENCED CODE1 STATUS2
`API
`1
`Adequate
`
`DATE
`REVIEW
`COMPLETED
`09/16/11
`
`10867
`
`II
`
`Apotex
`
`COMMENTS3
`
`Review by
`W.Adams
`
`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)
`3 Include reference to location in most recent CMC review
`
`
`
`
`
`
`B.
`
`Other Supporting Documents:
`
`Doc #
`IND 45,724
`
`OWNER
`ApoPharma
`
`ITEM
`REFERENCED
`Ferriprox
`
`STATUS
`active
`
`DATE REVIEW
`COMPLETED
`
`
`
`
`
`COMMENTS
`
`CMC Review #1
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`Page 6 of 62
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`CMC REVIEW OF NDA 21-825
`CMC Review Data Sheet
`
`CONSULTS/CMC-RELATED REVIEWS:
`
`
`18.
`
`
`CONSULTS
`Biometrics
`Clinical
`NonClinical
`ClinPham
`EES
`
`REVIEWER
`Q.Xu
`G.Shashaty
`Y.Chopra
`J.Grillo
`DMPQ
`
`Biopharm
`ODS/DMEPA
`EA
`
`T.M.Chen
`L.Holmes
`W.Adams
`
`Maternal Health L.Sahin
`
`
`DATE
`09/16/11
`09/16/11
`Pending Darrts
`09/16/11
`
`
`Pending Darrts
`07/11/11
`---
`
`08/16/11
`
`STATUS/
`CONCLUSION
`Adequate
`Adequate
`
`Adequate
`Pending
`
`Adequate
`Adequate
`---
`
`Adequate
`
`COMMENTS
`
`
`
`
`
`GMP inspection of DP mfg &
`control site started 09/19/11
`
`
`Categorical Exclusion granted in
`CMC Review 01
`
`
`CMC Review #1
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`
`CMC REVIEW OF NDA 21-825
`Executive Summary Section
`The CMC Review for NDA 201532
`
`The Executive Summary
`
`I.
`
`Recommendations
`
`
`
`A.
`
`Recommendation and Conclusion on Approvability
`
`
`
`From a CMC standpoint, this application is recommended for approval pending the receipt of an
`overall acceptable recommendation from the Office of Compliance. The submission is complete
`and all other CMC review issues have been resolved.
`
`Insert the following language into the action letter: Based on the stability data provided in your
`application, the drug product is granted a 24-month expiry when stored at USP controlled room
`temperature 20-25ºC (68-77ºF); excursions permitted to 15-30ºC (59-86ºF).
`
`
`
`
`None
`
`II.
`
`B. Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`Summary of CMC Assessments
`
`A.
`
`Description of the Drug Product(s) and Drug Substance(s)
`
`
`
`Proposed in this application is Ferriprox® (deferiprone) 500 mg oral tablets in a 100-count
`bottle. Ferriprox® is currently marketed in Europe and Australia. The application has been
`granted orphan drug and fast track status, and was accepted as a rolling submission.
`
`
`
`
`
`
`
` Subsequent amendments included CMC
`reviewable units for drug substance and drug product. The application has also been updated to
`include an additional drug substance supplier.
`
`Drug Substance
`Deferiprone (3-hydroxy-1,2-dimethylpyridin-4-one) is a bidentate iron chelator that
`preferentially binds ferric ions into a 3:1 (deferiprone: iron) complex at low pH. Bulk drug
`substance is a white to pink crystalline powder.
`
`
`
`Deferiprone is highly soluble in water at pH 1-7.5 and has high permeability, thus is a BCS class
`1 drug. Structure elucidation studies show the material is prepared
`
`.
`
`CMC Review #1
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`Page 8 of 62
`
`Reference ID: 3020615
`
`(b) (4)
`
`(b) (4)
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`(b) (4)
`
`

`

`
`
`
`
`
`
`Manufacture is by
`
`
`CMC REVIEW OF NDA 21-825
`Executive Summary Section
`
`
`
`
`
`
`
`
`. Manufacture and control of bulk process at each proposed site is described in
`Apotex, Inc.’s type II DM 10867. A letter of authorization to this file is provided. The DMF has
`been reviewed and found adequate to support approval of this application.
`
`Drug substance specifications for release from the manufacturer site and for acceptance at the
`single drug product manufacturing site differ in some of the non-chromatographic analytical
`methods, but the tests and criteria are identical. Testing is to be performed at each of these four
`sites or by contract laboratories. Testing is for identity, melting range, residue on ignition, heavy
`metals, water content, assay, residual solvents, related compounds (specified, unspecified and
`total impurities), bulk density, tapped density, particle size and
`. The HPLC
`methods for assay and related substances were revised after NDA submission. Each analytical
`method has been described completely and in sufficient detail. Acceptable method validation
`studies have been submitted for each non-compendial analytical method at their site of use.
`
`The proposed acceptance criteria for residual solvents, total impurities and water content are
`supported by batch analysis data. The proposed limits for specified impurity
`and
` are justified based on referenced safety studies. The proposed criteria for
`particle size, tapped density and bulk density are established to assure efficient tablet
`manufacture. Criteria for the other tests are justified based on data observed to date. Batch
`analysis data is provided for commercial-scale lots representing material manufactured since
`1993 and at each of the proposed manufacturing sites.
`
`Since there are no USP reference standards for this drug, samples taken from specified
`commercial lots without further processing are designated as the primary and secondary
`reference standard materials. These materials have been characterized and were used in the
`structure elucidation studies.
`
`.
`Packaging for storage and shipment is
`Descriptions and specifications for each packaging component and material of construction used
`at each of the manufacturing site are provided. Letters of authorization to the type III DMFs for
`the packaging component suppliers and their materials of construction have been provided.
`
`The primary stability studies are performed on multiple commercial-scale lots from each of the
`manufacturers stored in the proposed shipping container. Data is provided for storage at ICH
`long term conditions for 12-60 months; at ICH accelerated conditions for 6 months; and for
`exposure to UV and fluorescent light. Testing is for appearance, identity, assay, related
`substances and water content. Identity, appearance, assay and related substances did not change
`over time and no new impurities were detected. Water content increased slightly at high relative
`humidity. Supportive studies of drug substance with protective packaging for extended exposure
`to room temperature and short term exposure to high heat, high humidity and light show the
`same stability trends as the primary studies. Stress and forced degradation studies of unprotected
`
`
`
`CMC Review #1
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`Page 9 of 62
`
`Reference ID: 3020615
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`CMC REVIEW OF NDA 21-825
`Executive Summary Section
`
`
`
`
`
`
`solid and aqueous solutions show the drug molecule is slightly sensitive to
`. Degradants from these studies are not identified. The applicant proposes a retest
` for the Apotex Pharmachem and
`period of
`
` sites, and a
`retest period for the
` site with a label storage statement is USP CRT. The
`post approval stability protocol and commitment to continue the stability studies is acceptable.
`
`Drug Product
`Ferriprox® is a white to off white, capsule-shaped, immediate release, film-coated tablet
`containing 500 mg deferiprone. The tablet is imprinted with “APO” over “500” with a
`functional score on one side and plain on the other. The scoring is intended to facilitate breaking
`the tablet into two equal halves.
`
`Drug product development and investigational formulations for 100 mg, 250 mg and 500 mg
`tablets are summarized. The difference between the phase 3 and the commercial tablets is the
`. A
`Quality by Design approach was not used and a design space for the manufacturing process steps
`has not been developed. Tablet divisibility is adequately addressed by studies using
`developmental lots; by process validation studies addressing blend uniformity; and by data from
`the supportive stability studies. Development of the dissolution method is addressed in studies
`using developmental and clinical lots. An acceptable dissolution criterion has been proposed
`based on submitted drug release profile data.
`
`Unit and batch formulations are provided. The excipients are Microcrystalline Cellulose,
`Magnesium Stearate, and Colloidal Silicon Dioxide in the cores; and Hypromellose
`,
`Polyethylene Glycol
` and Titanium Dioxide in the film coating. All
`excipients are USP/NF grade materials. Dry excipients are purchased from major suppliers and
`each has an internet website. No excipient is novel or of human origin.
`
` Excipient specifications are the current USP/NF monograph for
` is prepared at the tablet manufacturing site. Certificates of
`each material.
`analysis for the excipients lots used in the stability and 3 biolots are provided. Contract
`laboratories for excipient testing may be used.
`
`Tablet manufacture, control, packaging, release testing, and stability testing are performed at
`Apotex, Inc. (Etobicoke, Canada). Tablets may be packaged and labeled at Apotex, Inc.
`(Toronto, Canada). The tablet manufacture process is
`
`
`. The manufacturing process,
`process parameters and in-process controls are acceptable and are described in sufficient detail.
`A narrative description and process flow diagram are included. Tablet
` is not
`proposed. Executed batch records and supporting analytical information are provided for the
`clinical and stability batches.
`
`The release specification includes testing for identity, average tablet weight, dissolution, content
`uniformity/assay, and degradants (unspecified and total. The tests are adequate to establish
`identify, purity and strength of the drug product. The methods for assay and related substances
`were revised after NDA submission. Descriptions of the analytical methods are complete and
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`CMC Review #1
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`Reference ID: 3020615
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`CMC REVIEW OF NDA 21-825
`Executive Summary Section
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` and the drug substance standards.
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`provided in sufficient detail. Representative spectra and chromatograms have been provided.
`Validation studies for the non-compendial methods are complete and establish the methods as
`adequate for the intended use.
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`The proposed acceptance criteria are justified based on batch analysis data submitted for batches
`used in clinical and stability studies , and safety information. The absence of testing for residual
`moisture content and microbial limits is justified based on historical batch analysis data.
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`The proposed reference standards are
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`The proposed commercial presentation is 100 tablets in a 120cc round, white HDPE bottle with a
`child resistant closure having a silver foil/foam cap liner; an aluminum foil
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`induction innerseal; and an extended content label (ECL). The ECL is a patient information
`leaflet which may be removed or re-applied to the bottle by the patient. The innerseal is
`constructed with a “Lift N’Peel” tab for easy removal. There is no carton for the bottle.
`Suppliers and materials of construction for each packaging component are identified and an
`acceptance specification for each component is provided. Letters for authorization for the type
`III DMFs for the component suppliers and their materials of construction are provided.
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`Primary stability studies are performed on commercial-scale white tablets in the proposed 100-
`count package and in a 1000-count version of the same package stored at ICH long term
`conditions for 12-60 months, ICH intermediate conditions for 60 months and ICH accelerated
`conditions for 6 months. The lots were tested for identity, appearance, assay, degradants, and 1-
`point dissolution. Some lots were also tested for microbial limits after 60 months. The results
`show no change in test values over time, no microbial limits failures at release and no formation
`of new degradants. Supportive stability studies were performed on pink tablets stored in 100-
`count and 1000-count packages at 25-30oC/ambient RH, ICH accelerated and light stress
`conditions for 36 months, 6 months, and 3 months, respectively. The results from all studies
`show no change in test values over time and the formation of no new degradants. Since multiple
`drug substance sources are proposed, the approved expiry period is to be based on the studies for
`tablets manufactured with each drug substance supplier. The application is to be approved with
`an initial expiry period of 24 months with storage at controlled room temperature. The post
`approval stability protocol and commitment are acceptable.
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`The applicant has requested a categorical exclusion from the environmental assessment
`requirements under 21 CFR 25.31(b) in that the amount of drug introduced into the environment
`is less than 1 ppb per year. A calculation if expected introduction concentration is included.
`The request is considered to be justified.
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`Draft container label and patient information leaflet are provided. The proposed trade name,
`established name, storage condition statement and other CMC information are acceptable. Final
`revisions to the CMC information in the patient information leaflet have already been requested.
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`The Overall EES Conclusion was Pending dated 11 Jul 2011. GMP inspection of the drug
`product manufacturing site is pending. All sites were re-submitted in the current review clock
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`CMC Review #1
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`Page 11 of 62
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`Reference ID: 3020615
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`CMC REVIEW OF NDA 21-825
`Executive Summary Section
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`for confirmation of cGMP status, and an updated overall recommendation has not yet been
`received.
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`B.
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`Description of How the Drug Product is Intended to be Used
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`Deferiprone formulated as Ferriprox® is indicated for the treatment of patients with excessive
`body iron stores due to chronic transfusion therapy. The dose is 25-33 mg/Kg body weight taken
`orally three times daily for a total dose of 75-
` mg/Kg body weight. The maximum safe dose
`is
` mg/Kg body weight/day. Doses are to be rounded to the nearest half tablet.
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`C.
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`Basis for Approvability or Not-Approval Recommendation
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`The proposed application is considered to be adequate for APPROVAL from the CMC
`perspective, pending the receipt of an overall acceptable recommendation from the Office of
`Compliance. Complete and acceptable CMC information has been provided.
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`III. Administrative
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`A.
`Reviewer’s Signature: (See appended electronic signature page)
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`William M. Adams
`DNDQA I/CMC Reviewer
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`B.
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`Endorsement Block: (See appended electronic signature page)
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`Sarah Pope Miksinski, Ph.D.
`DNDQA I/Branch Chief
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`C.
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`CC Block: (entered electronically in Darrts)
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`DNDQA I/PMQ/T.V.Lambert
`DNDQA I/CMC Lead/J.Brown
`DMIHP/RPM/M.Miller
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`CMC Review #1
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`Page 12 of 62
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`Reference ID: 3020615
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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/
`----------------------------------------------------
`
`WILLIAM M ADAMS
`09/26/2011
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`SARAH P MIKSINSKI
`09/27/2011
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`Reference ID: 3020615
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`CHEMISTRY REVIEW
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`NDA 21-825
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`Ferriprox
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`ApoPharma, Inc.
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`William M. Adams
`Office of New Drug Quality Assurance (ONDQA)
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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
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`The Executive Summary .........................................................................................8
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`I. Recommendations......................................................................................................................6
`A. Recommendation and Conclusion on Approv