CENTER FOR DRUG EVALUATION AND
`
`CENTER FOR DRUG EVALUATION AND
`RESEARCH
`RESEARCH
`
`
`
`
`
`APPLICATION NUMBER:
`22-272
`22-272
`
`APPLICA TION NUMBER:
`
`CHEMISTRY REVIEW(S)
`CHEMISTRY REVIEW! S}
`
`
`
`
`
`
`
`

`

`MEMORANDUM: DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC
`HEALTH SERVICE
`FOOD AND DRUG ADMINISTRATION
`CENTER FOR DRUG EVALUATION AND RESEARCH
`
`
`
`DATE:
`
`TO:
`
`
`
`18-FEB-2010
`
`N 22272 File for OxyContin® (oxycodone
`hydrochloride controlled-release) Tablets
`
`
`FROM:
`
`Craig M. Bertha, Ph.D.
`Chemistry Reviewer
`ONDQA, Division I, Branch II
`
`THROUGH: Prasad Peri, Ph.D.
`
`
`Acting Branch Chief
`
`
`ONDQA, Division I, Branch II
`
`SUBJECT: Review of CMC-related labeling in the 04-FEB-2010, amendment of N22272
`
`BACKGROUND: The DAARP sent a complete response letter to the applicant of N22272 dated
`30-DEC-2009. There were no remaining CMC-related issues that were to be addressed by the
`applicant and the CMC team had recommended in the fourth CMC review dated 23-JUL-2009,
`that the application be approved. The latest resubmission contains labeling and labels that are
`revised from those last reviewed by the CMC team in the third CMC review dated 28-APR-2009.
`The revisions to the labeling and labels is the subject of this fifth CMC review.
`
`EVALUATION: The package insert (PI) that was included in the 04-FEB-2010, amendment
`includes some revisions relative to the labeling in the 27-MAR-2009, amendment, which was the
`subject of the third CMC review. Specifically, in all places in the new PI, with the exception of
`the Structured Product Labeling data table and the header on the first page, the dosage form
`descriptor is “controlled-release tablets.” In the exceptions, it is listed as an “extended-release
`tablet.” Recall that ONDQA recommended to the clinical division that the applicant be asked to
`change the dosage form descriptor to “extended-release tablets” to be consistent with current
`policy. The DAARP decided that this would not be requested of Purdue as it may lead to
`confusion when the product was approved as a replacement for the older approved OxyContin,
`which currently is described as a “controlled-release tablet.”
`
`In the current USP there is a monograph entitled “Oxycodone Extended-Release Tablets.”
`Because of differences in the acceptance criteria for dissolution for Purdue’s current reformulated
`OxyContin, this product would not be able to meet the acceptance criteria in the USP
`monograph. Specifically, the new formulations of OxyContin will meet the following
`dissolution acceptance criteria:
`
`
`

`

`NDA 22272
`
`
`Review of Labeling Revisions
`
`p. 2
`
`15
`
`20
`
`30
`
`40
`
`60
`
`80
`
`
`Drug released (%)
`Time/strength (mg) 10
`1 hour
`
`4 hours
`
`12 hours
`
`
`These acceptance criteria are different from what is in the USP for the 10, 20, 40, and 80 mg
`strength of oxycodone extended-release tablets, i.e.,
`
`
`FOR TABLETS LABELED TO CONTAIN 10 MG:
`
`Time (hours) Amount dissolved
`1
`between
`4
`between
`
`12
`not less than
`FOR TABLETS LABELED TO CONTAIN 20 MG:
`
`Time (hours) Amount dissolved
`1
`between
`4
`between
`
`12
`not less than
`FOR TABLETS LABELED TO CONTAIN 40 MG:
`
`Time (hours) Amount dissolved
`1
`between
`4
`between
`
`12
`not less than
`FOR TABLETS LABELED TO CONTAIN 80 MG:
`
`Time (hours) Amount dissolved
`1
`between
`4
`between
`12
`not less than
`
`
`
`
`In general, it is seen that at both 1 and 4 hours, the target in vitro release for the Purdue 10, 20,
`40, and 80 mg reformulated product is less than the target represented by the USP monograph.
`However, at 12 hours, all acceptance criteria require not less than
` release.
`
`Since the applicant is not using the monograph name for their reformulated product, and the
`clinical division finds this to be acceptable, there is no requirement that the applicant state in the
`labels and labeling that the drug product does not meet the USP monograph for Oxycodone
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22272
`
`
`Review of Labeling Revisions
`
`p. 3
`
`Extended-Release Tablets. Nevertheless, they have added the following statement to the
`DESCRIPTION section:
`
`
`
`To be more precise, this statement should be revised to the following:
`
`
`‘OxyContin 10 mg, 15 mg, 20 mg, 30 mg, 40 mg, 60 mg, and 80 mg tablets, as described
`in this section are not tested according to and do not meet the “Oxycodone Hydrochloride
`Extended-Release Tablets” monograph in the USP.’
`
`
`Alternatively, the applicant could just remove reference to the USP monograph for Oxycodone
`Hydrochloride Extended-Release Tablets altogether in the PI as the USP specifically states:
`
`
`“The identity of an official article, as expressed by its name, is established if it conforms
`in all respects to the requirements of its monograph and other relevant portions of the
`compendia. The FD&C Act stipulates that an article may differ in strength, quality, or
`purity and still have the same name if the difference is stated on the article's label. FDA
`requires that names for articles that are not official must be clearly distinguishing and
`differentiating from any name recognized in an official compendium. Official
`preparations (a drug product, a dietary supplement including nutritional supplements, or a
`finished device) may contain additional suitable ingredients. (See General Notices.)”
`
`
`Comment: Revise the DESCRIPTION section of the labeling to state that the new OxyContin
`formulations ‘do not meet the “Oxycodone Hydrochloride Extended-Release Tablets”
`monograph in the USP.”’ Alternately, remove the statement completely as you are not using the
`name from the official monograph.
`
`Other changes to the PI include the description of the dosage form in the DOSAGE FORMS
`AND STRENGTHS section of the HIGHLIGHTS portion. In the previous version the tablets
`were described as
`whereas in the new version, the tablets are described as
`“controlled-release.” This change is acceptable and complies with the regulation 21 CFR
`201.57(a)(8). Likewise, in the full DOSAGE FORMS AND STRENGTHS section, the tablets
`are no longer described as
` but are characterized as “film-coated.” This section is
`compliant with 21 CFR 201.57(c)(4).
`
`The only significant non-editorial change made to the DESCRIPTION section is the removal of
`the following statement:
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22272
`
`
`Review of Labeling Revisions
`
`p. 4
`
`
`In addition, as already mentioned, the section now includes a statement indicating that the drug
`product does not comply with the USP monograph (see comment to be forwarded to the
`applicant above). Overall, this section is compliant with the information required by 21 CFR
`201.57(c)(12).
`
`The only change that has been made to the HOW SUPPLIED/STORAGE AND HANDLING
`section is that the tablets are no longer described as
` The section still complies with
`21 CFR 201.57(c)(17).
`
`The amendment also provides updated mock-up bottle labels for each of the strengths. Relative
`to the last set of labels that were reviewed by the CMC team from the 27-MAR-2009,
`amendment, the new versions include the following message:
`
`
`
`The last reviewed version of the bottle labels included a clear indication of where the product lot
`number and expiration date would appear. That is no longer clear on the current revised
`versions, as can be seen in the example of the 10 mg strength label reproduced below:
`
`
`
`
`Comment: For each strength of the drug product, revise and resubmit the mock-ups of the bottle
`labels such that it is clear where the lot number and expiration date will be located.
`
`
`
`
`
`
`
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`NDA 22272
`
`
`Review of Labeling Revisions
`
`p. 5
`
`
`
`The only other notable change is the removal of the pictures of the actual dosage forms that had
`appeared on earlier versions of the bottle labels. Such pictures are not required by 201.100(b).
`
`RECOMMENDATION: The following comments should be forwarded to the applicant by the
`PM. If there are other labeling comments to be forwarded by other members of the review team,
`these may be included with those rather than being sent under separate cover.
`
`
`1. Revise the DESCRIPTION section of the labeling to state that the new OxyContin
`formulations ‘do not meet the “Oxycodone Hydrochloride Extended-Release Tablets”
`monograph in the USP.”’ Alternately, remove the statement completely as you are not
`using the name from the official monograph.
`
`2. For each strength of the drug product, revise and resubmit the mock-ups of the bottle
`labels such that it is clear where the lot number and expiration date will be located.
`
`
`
`
`
`________________________
`Craig M. Bertha, Ph.D.
`Chemistry Reviewer
`
`
`
`
`
`
`
`cc:
`Orig. NDA 22-272
`C.Bertha/ONDQA//Reviewer/2/18/10
`PPeri/ONDQA/Acting Branch Chief________________
`DChristodoulou/ONDQA/PAL
`LBasham/DAARP/Regulatory PM
`
`
`(b) (4)
`
`

`

`Application
`Type/Number
`--------------------
`NDA-22272
`
`Submission
`Type/Number
`--------------------
`ORIG-1
`
`Submitter Name
`
`Product Name
`
`--------------------
`PURDUE PHARMA
`INC
`
`------------------------------------------
`OXYCONTIN
`
`---------------------------------------------------------------------------------------------------------
`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
`02/19/2010
`
`PRASAD PERI
`02/19/2010
`I concur
`
`

`

`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 22-272
`
`
`OxyContin® (oxycodone hydrochloride controlled-release)
`Tablets
`
`
`
`Purdue Pharma L.P.
`
`
`
`
`Craig M. Bertha, Ph.D.
`ONDQA/Division I/Branch 2
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`
`
`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..........................................................9
`C. Basis for Approvability or Not-Approval Recommendation..........................................................10
`
`III. Administrative.........................................................................................................................10
`A. Reviewer’s Signature......................................................................................................................10
`B. Endorsement Block.........................................................................................................................10
`C. CC Block........................................................................................................................................10
`
`Chemistry Assessment.......................................................................................... 11
`
`
`
`
`Page 2
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`Chemistry Review Data Sheet
`
`
`
`
`1. NDA 22-272
`
`
`2. REVIEW #: 4
`
`
`3. REVIEW DATE: 20-JUL-2009
`
`
`4. REVIEWER: Craig M. Bertha, Ph.D.
`
`
`5. PREVIOUS DOCUMENTS:
`
`
`Document Date
`Previous Documents
`
`
`Original
`28-NOV-2007 (assigned 17-DEC-2007)
`Amendment (stability update)
`18-DEC-2008 (assigned 24-DEC-2007)
`Amendment (stability update)
`15-FEB-2008 (assigned 15-FEB-2008)
`Amendment (response to 74-day letter)
`06-MAR-2008 (assigned 10-MAR-2008)
`Amendment (individual dissolution data)*
`07-MAR-2008 (assigned 10-MAR-2008)
`Amendment (response to 13-FEB-2008 CMC DR)
`13-MAR-2008 (assigned 17-MAR-2008)
`Amendment (response to 05-MAR-2008 IR)*
`17-MAR-2008 (assigned 19-MAR-2008)
`Amendment (response to CMC IR of 24-MAR-2008)
`25-MAR-2008 (assigned 27-MAR-2008)
`Correspondence (summary of tamper resistance report for AC)
`25-MAR-2008 (assigned 27-MAR-2008)
`Amendment (CMC data supporting reformulated 60 and 80 mg
`27-MAR-2009 (assigned 10-APR-2009)
`strengths)
`*Evaluated in consult review from Arzu Selen, Ph.D., Associate Director of Pharmaceutics.
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`
`Amendment (Response to IR letter of 01-MAY-2009)
`Amendment (Provision of SAS stability files for statistician)
`Amendment (stability update for 60 and 80 mg strengths)
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`Document Date (from Form 356h)
`
`13-MAY-2009
`29-MAY-2009
`15-JUN-2009
`
`Name: Purdue Pharma L.P.
`Address: One Stamford Forum
`Stamford, CT 06901-3431
`
`Page 3
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Representative: Patricia R. Mayer, Ph.D.
`Senior Director, U.S. Regulatory Affairs
`Telephone: 203-588-7558
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: OxyContin® Tablets, extended release
`b) Non-Proprietary Name (USAN): oxycodone hydrochloride
`c) Code Name/# (OGD only):
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 3
`• Submission Priority: P
`
` tablet, extended release (code 510)1
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1); refer to cross reference to
`N20-553 in module 1 or original submission.
`
`
`10. PHARMACOL. CATEGORY: opioid analgesic
`
`
`11. DOSAGE FORM:
`
`
`12. STRENGTH/POTENCY: 10, 15, 20, 30, 40, 60, and 80 mg/tablet
`
`
`13. ROUTE OF ADMINISTRATION: oral, code 001
`
`
`14. Rx/OTC DISPENSED: _X__Rx ___OTC
`
`
`15. SPOTS (SPECIAL PRODUCTS ON-LINE TRACKING SYSTEM):
` SPOTS product – Form Completed
`
` X Not a SPOTS product
`
`
`
`
`
`
`
`
`
`
`
`
`
`1The CDER Data Standards Manual does not include a dosage form description for controlled-release tablets, but
`does include “tablet, extended release” with code 510. The product of N20-553 has the approved name:
`OxyContin® (oxycodone hydrochloride controlled-release) tablets. As per the instructions from Ali Al Hakim,
`Ph.D., Branch Chief, at the 09-JUN-2009 meeting, the CMC reviewer informed the review team of the ONDQA
`recommendation that the applicant change the drug product established name to “oxycodone hydrochloride extended
`release tablets,” to be consistent with current naming policy.
`
`Page 4
`
`

`

`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`16. CHEMICAL NAME, STRUCTURAL FORMULA, MOLECULAR
`FORMULA, MOLECULAR WEIGHT:
`
`
`
`
`
`
`H
`
`Me
`
`N
`
`HO
`
`O
`
`O
`
`MeO
`
`HCl
`
`
`
`
`
`
`C18H21NO4·HCl (crystalline form is actually a monohydrate)
`351.83 g/mol or 369.84 g/mol as monohydrate
`
`
`4, 5-epoxy-14-hydroxy-3-methoxy-17-methylmorphinan-6-one hydrochloride
`
`Molecular formula:
`Molecular weight:
`
`17. RELATED/SUPPORTING DOCUMENTS:
`
`
`ITEM REFERENCED
`
`CODE1
`3
`
`STATUS2 DATE REVIEW
`COMPLETED
`Adequate
`29-JUN-2007
`
`4
`
`Adequate
`
`
`
`A. Supporting DMFs:
`
`
`DMF # TYPE HOLDER
`
`2
`
`4
`
`3
`
`3
`
`3
`
`Adequate
`
`12-JAN-2005
`
`3
`
`4
`
`4
`
`Adequate
`
`Adequate
`
`
`
`
`
`
`
`3
`1 Action codes for DMF Table:
`1 – DMF Reviewed.
`Other codes indicate why the DMF was not reviewed, as follows:
`2 –Type 1 DMF
`
`Adequate
`
`4
`
`Page 5
`
`COMMENTS3
`Reviewed for another
`solid oral dosage form
`product
`Applicant claims on p. 3
`of 73 of QOS (orig.
`submission) that the non-
`functional tablet coatings
`have not changed from
`those previously
`approved for the
`previously formulated
`product. Thus, no further
`review is necessary. For
`for 60 and 80 mg
`strengths, sufficient
`information is provided
`in the 27-MAR-2009,
`amendment.
`In addition, no changes
`have been made to the
`CCS as per P.7, relative
`to the CCS of N20-553.
`See above.
`
`See above.
`
`See above.
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`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 are 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 #
`
`OWNER
`
`
`
`
`
`
`
`
`
`ITEM
`REFERENCED
`
`DATE REVIEW
`COMPLETED
`
`STATUS
`
`
`
`
`
`
`
`
`
`
`
`
`COMMENTS
`
`
`
`
`
`
`
`
`
`
`C. Related Documents:
`
`
`DOCUMENT APPLICATION
`NUMBER
`NDA
`20-553
`
`
`
`
`
`
`
`OWNER
`Purdue Pharma
`L.P.
`
`
`
`DESCRIPTION/COMMENT
`original application for OxyContin® Tablets, as
`supplemented (original approval 12-DEC-1995)
`
`
`
`
`
`18. CONSULTS/CMC-RELATED REVIEWS:
`
`
`
`CONSULTS
`
`SUBJECT
`
`Statistics
`
`Stability data and
`expiry proposals
`
`EES
`
`Pharm/Tox
`
`Biopharm
`(ONDQA)
`
`
`
` degradant
`allowance in DP
`-residual
`
` in
`
`excipient
`4 hour dissolution
`acceptance criteria
`
`
`
`DATE
`FORWARDED
`17-JAN-2008 (10-40 mg)
`15-FEB-2008 (10-40 mg)
`20-MAR-2008 (10-40 mg)
`
`23-APR-2009 (60&80 mg)
`
`19-MAY-2009 (10-40 mg)
`
`
`
`29-JUN-2009 (60&80mg)
`
`10- and 16-JAN-2008, and
`23-APR-2009
`23-APR-2009
`
`
`18-MAY-2009 (e-mail)
`
`STATUS/
`REVIEWE
`R
`
`
`
`Final/M. Shen,
`Ph.D.
`Final/M. Shen,
`Ph.D.
`Final/M. Shen,
`Ph.D.
`
`
`Final/M. Shen,
`Ph.D.
`Final
`
`Final/E. Bolan,
`Ph.D.
`
`Final/E. Bolan,
`Ph.D.
`
`COMMENTS
`
`24-DEC-2007, amendment adds 9 month stability data;
`15-FEB-2008, amendment adds 12 month data; 20-
`MAR-2008, amendment of dissolution acceptance
`criteria at 4 h test point
`23-APR-2009, amendment provides for two new
`strengths (60 & 80 mg) with 9 months stability data
`13-MAY-2009, amendment adds 18 and 24 month data
`for 10-40 mg strengths
` bottle cts);
` 100, and
`Note that 29-MAY-2009, amendment provided the
`data from the 13-MAY-2009, in SAS format
`15-JUN-2009, amendment adds 12-24 month stability
`data
`OC Recommendation for application is
`ACCEPTABLE
`See p. 45 of CMC review #3.
`
`
`See p. 12 of CMC review #4.
`
`17-JAN-2008
`
`Final/Arzu
`Selen, Ph.D.
`
`Original acceptance criteria proposed were wider than
` of LC for the 4 hour time-point, thus, as per ICH
`
`Page 6
`
`(b) (4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b) (4)
`
`(b)
`(4)
`
`(b)
`(4)
`
`

`

`
`
`
`
`
`LNC
`Methods
`Validation
`DMETS/DDMAC
`EA
`Microbiology
`
`
`
`10, 15, 20, 30, 40
`mg strengths
`
`N/A
`N/A
`
`Labeling/labels
`N/A
`N/A
`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Q6A, bioavailability data were needed in support of the
`acceptance range; 07- and 17-MAR-2008, amendments
`are responses forwarded to consult reviewer; see
`review of new proposed acceptance criteria on p. 14 of
`CMC review #2
`
`See p. 61 of CMC review #1
`
`Forwarded by DAARP PM
`See p. 64 of CMC review #1
`See p. 26 of CMC review #1
`
`
`
`
`
`
`
`
`Page 7
`
`

`

`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`
`The Chemistry Review for NDA 22-272
`
`The Executive Summary
`
` I. Recommendations
`
`A.
`Recommendation and Conclusion on Approvability
`
`The application is recommended for approval from the CMC perspective.
`
`To be compliant with current ONDQA policy, it is recommended that the
`applicant change the drug product established name to “oxycodone hydrochloride
`extended release tablets” from “oxycodone hydrochloride controlled-release
`tablets.”
`
`
`B.
`
`II.
`
`Recommendation on Phase 4 (Post-Marketing) Commitments, Agreements,
`and/or Risk Management Steps, if Approvable
`
`N/A
`
`Summary of Chemistry Assessments
`
`A. Description of the Drug Product(s) and Drug Substance(s)
`
`The drug product is OxyContin® (oxycodone hydrochloride controlled-release)
`Tablets and is proposed in strengths of 10, 15, 20, 30, 40, 60, and 80 mg/tablet.
`The tablets are for oral administration and are packaged (all strengths) in 75 cc
`HDPE bottles with child resistant caps. The drug product formulation consists of
` polyethylene oxide (
` by
`oxycodone hydrochloride
` The tablets are formed
`weight) and magnesium stearate
` by weight
`by
`
`
`
`
`
`
`
`
` The
`applicant claims to have demonstrated the bioequivalence of these newly
`formulated products to the OxyContin presently approved and marketed under
`N20-553.
`
`Review of the preliminary report on the applicant’s evaluation of the comparative
`resistance of the newly formulated and the currently marketed product to physical
`and chemical manipulation lead to the conclusion that the newly formulated
`product is more manipulation resistant than the current marketed product.
`However, the determination of the relevance of the in vitro preparation conditions
`
`Page 8
`
`(b) (4)
`
`(b) ( )
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`used in the evaluation relative to those used by abusers, and the likely in vivo
`results of usage of such preparations is beyond the scope of this CMC review.
`The polyethylene oxide polymer is
` thus it
`is expected that the formulation would not be susceptible to dose dumping. The is
`supported by the in vitro dissolution data collected
`
`
`The drug substance is oxycodone hydrochloride monohydrate and it is obtained
`from a single source that assures the level of the
`
` is
` The particle size of the
`drug substance is controlled, although development studies have not shown that
`variation in particle size leads to variation in drug product performance (e.g.,
`dissolution). Studies reported in the original submission were not able to
`completely rule out the possibility
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
` The most significant variable that impacts the product dissolution is
`the strength of the tablet. This is not unexpected since the different strengths are
`not compositionally proportional with respect to the ratio of the active to the
`excipient components that provide the extended release properties.
`
`
`The application contained data from a single near-commercial scale
`batch of each strength, manufactured at the commercial site, and using a process
`analogous to that intended for commercial production. These batches were used
`for both the primary stability studies and for the pivotal bioequivalence studies.
`
`
`B. Description of How the Drug Product is Intended to be Used
`
`The labeling indicates that this opioid analgesic should use low initial doses in
`patients that are not opioid tolerant and especially for those patients receiving
`concurrent treatment with muscle relaxants, sedatives, or other central nervous
`system active medications. The 60 and 80 mg strengths are said to be for use by
`opioid tolerant patients only. All of the strengths are to be taken orally at 12 hour
`intervals. Tablets are to be swallowed whole and are not to be cut, broken,
`chewed, or crushed, as there is the potential to obtain a fatal dose otherwise. The
`strengths are 10, 15, 20, 30, 40, 60, and 80 mg.
`
`The application has provided 24 months of stability data for all strengths of the
`reformulated drug product. An expiry of 24 months is proposed for all strengths
`and is acceptable.
`
`
`Page 9
`
`(b) (4)
`
`(b) (4)
`
`(b) ( )
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`
`
`
`CHEMISTRY REVIEW
`
`
`
`
`
`
`
`The storage conditions recommended in the labeling are for room temperature
`storage in tight containers and with protection from light. The stability data are
`supportive of these recommendations.
`
`C. Basis for Approvability or Not-Approval Recommendation
`
`N/A
`
`III. Administrative
`
`A. Reviewer’s Signature
`
`
`
`B. Endorsement Block
`
`
`
`
`
`
`
`
`
`CBertha/ONDQA/Reviewer/7/20/09
`AAlHakim/ONDQA/DIV I//Branch II/Branch Chief___________
`
`
`C. CC Block
`
`LBasham/DAARP/Regulatory PM
`JChen/DAARP/MO
`SAlHabet/OCP/Biopharm
`DMellon/DAARP/Pharm/Tox TL
`EBolan/DAARP/Pharm/Tox
`DChristodoulou/ONDQA/DIV I/Branch II/PAL
`DHenry/ONDQA/DIV I/Regulatory PM
`MShen/DBVI/Math. Stat.
`
`Page 10
`
`9 pp withheld in full immed. after this page as (b)(4) CCI/TS.
`
`

`

`---------------------------------------------------------------------------------------------------------------------
`This is a representation of an electronic record that was signed electronically and
`this page is the manifestation of the electronic signature.
`---------------------------------------------------------------------------------------------------------------------
` /s/
`---------------------
`Craig Bertha
`7/20/2009 07:31:57 AM
`CHEMIST
`
`Ali Al-Hakim
`7/23/2009 11:07:45 AM
`CHEMIST
`
`

`

`
`
`
`
`
`
`
`
`
`CHEMISTRY REVIEW
`
`NDA 22-272
`
`
`OxyContin® (oxycodone hydrochloride controlled-release)
`Tablets
`
`
`
`Purdue Pharma L.P.
`
`
`
`
`Craig M. Bertha, Ph.D.
`ONDQA/Division I/Branch 2
`
`
`
`
`
`
`
`
`
`
`
`
`

`

`
`
`
`
`CHEMISTRY REVIEW
`
`
`
`Table of Contents
`
`
`Table of Contents .....................................................................................................2
`
`Chemistry 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 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..........................................................9
`C. Basis for Approvability or Not-Approval Recommendation..........................................................10
`
`III. Administrative.........................................................................................................................10
`A. Reviewer’s Signature......................................................................................................................10
`B. Endorsement Block.........................................................................................................................10
`C. CC Block........................................................................................................................................10
`
`Chemistry Assessment.......................................................................................... 11
`
`Review Of Common Technical Document-Quality (Ctd-Q) Module 3.2:
`I.
`Body Of Data ......................................................................................................... 11
`
`S DRUG SUBSTANCE [oxycodone hydrochloride,
`
`]......................................................11
`
`P DRUG PRODUCT [oxycodone hydrochloride tablets, extended release].................................11
`P.1 Description and Composition of the Drug Product [oxycodone hydrochloride tablets, extended
`release]...........................................................................................................................................11
`P.2 Pharmaceutical Development [oxycodone hydrochloride tablets, extended release] ....................14
`P.3 Manufacture [oxycodone hydrochloride tablets, extended release]...............................................26
`P.4 Control of Excipients [oxycodone hydrochloride tablets, extended release] .................................33
`P.5 Control of Drug Product [oxycodone hydrochloride tablets, extended release] ............................36
`P.6 Reference Standards or Materials [oxycodone hydrochloride tablets, extended release] ..............45
`P.7 Container Closure System [oxycodone hydrochloride tablets, extended release]..........................46
`
`Page 2
`
`(b) (4)
`
`

`

`
`
`P.8 Stability [oxycodone hydrochloride tablets, extended release]......................................................46
`
`
`CHEMISTRY REVIEW
`
`A APPENDICES ...........................................................................................................................54
`A.1 Facilities and Equipment (biotech only)........................................................................................54
`A.2 Adventitious Agents Safety Evaluation.........................................................................................54
`A.3 Novel Excipients ...........................................................................................................................54
`
`R REGIONAL INFORMATION ..................................................................................................54
`R1 Executed Batch Records .................................................................................................................54
`R2 Comparability Protocols .................................................................................................................55
`R3 Methods Validation Package ..........................................................................................................55
`
`II. Review Of Common Technical Document-Quality (Ctd-Q) Module 1....................................55
`A. Labeling & Package Insert .............................................................................................................55
`B. Environmental Assessment Or Claim Of Categorical Exclusion ....................................................57
`
`
`
`
`Page 3
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`
`Chemistry Review Data Sheet
`
`
`
`
`1. NDA 22-272
`
`
`2. REVIEW #: 3
`
`
`3. REVIEW DATE: 28-APR-2009
`
`
`4. REVIEWER: Craig M. Bertha, Ph.D.
`
`5. PREVIOUS DOCUMENTS:
`
`
`Document Date
`Previous Documents
`
`
`Original
`28-NOV-2007 (assigned 17-DEC-2007)
`Amendment (stability update)
`18-DEC-2008 (assigned 24-DEC-2007)
`Amendment (stability update)
`15-FEB-2008 (assigned 15-FEB-2008)
`Amendment (response to 74-day letter)
`06-MAR-2008 (assigned 10-MAR-2008)
`Amendment (individual dissolution data)*
`07-MAR-2008 (assigned 10-MAR-2008)
`13-MAR-2008 (assigned 17-MAR-2008)
`Amendment (response to 13-FEB-2008 CMC DR)
`17-MAR-2008 (assigned 19-MAR-2008)
`Amendment (response to 05-MAR-2008 IR)*
`25-MAR-2008 (assigned 27-MAR-2008)
`Amendment (response to CMC IR of 24-MAR-2008)
`Correspondence (summary of tamper resistance report for AC)
`25-MAR-2008 (assigned 27-MAR-2008)
`*Evaluated in consult review from Arzu Selen, Ph.D., Associate Director of Pharmaceutics.
`
`
`
`6. SUBMISSION(S) BEING REVIEWED:
`
`
`Submission(s) Reviewed
`
`Amendment (CMC data supporting reformulated 60 and
`80 mg strengths)
`
`
`
`
`7. NAME & ADDRESS OF APPLICANT:
`
`
`
`
`
`Document Date
`
`27-MAR-2009 (assigned 10-APR-2009)
`
`Name: Purdue Pharma L.P.
`Address: One Stamford Forum
`Stamford, CT 06901-3431
`
`Page 4
`
`

`

`
`
`
`
`
`
`CHEMISTRY REVIEW
`Chemistry Review Data Sheet
`
`
`
`Representative: Patricia R. Mayer, Ph.D.
`Senior Director, U.S. Regulatory Affairs
`Telephone: 203-588-7558
`
`
`8. DRUG PRODUCT NAME/CODE/TYPE:
`
`a) Proprietary Name: OxyContin® Tablets, extended release
`b) Non-Proprietary Name (USAN): oxycodone hydrochloride
`c) Code Name/# (OGD only):
`d) Chem. Type/Submission Priority (ONDC only):
`• Chem. Type: 3
`• Submission Priority: P
`
` tablet, extended release (code 510)1
`
`
`
`9. LEGAL BASIS FOR SUBMISSION: 505(b)(1); refer to cross reference to
`N20-553 in module 1 or original submission.
`
`
`10. PHARMACOL. CATEGORY: opioid analgesic
`
`
`11. DOSAGE FORM:
`
`
`12. STRENGTH/POTENCY: 10, 15, 20, 30, 40, 60, and 80 mg/tablet
`
`
`13. ROUTE OF ADMINISTRATION: oral, code 00