Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 1 of 43 PageID #: 996
`
`IN THE UNITED STATES DISTRICT COURT
`FOR THE DISTRICT OF DELAWARE
`
`C.A. No. 16-1221 (LPS)
`
`PUBLIC - REDACTED VERSION
`
`))))))))))
`
`BAYER HEALTHCARE LLC AND BAYER
`HEALTHCARE PHARMACEUTICALS INC.,
`
`Plaintiffs,
`
`v.
`
`TEVA PHARMACEUTICALS USA, INC.,
`APOTEX CORP. and APOTEX, INC.
`
`Defendants.
`
`LETTER TO THE HONORABLE LEONARD P. STARK
`FROM KENNETH DORSNEY REGARDING DISCOVERY DISPUTE
`
`Dated: April 25, 2019
`
`Kenneth L. Dorsney (#3726)
`MORRIS JAMES LLP
`500 Delaware Avenue, Suite 1500
`Wilmington, DE 19801
`(302) 888-6800
`kdorsney@morrisjames.com
`
`Attorneys for Defendants Apotex Corp. and
`Apotex, Inc.
`
`10907646/1
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 2 of 43 PageID #: 997
`
`Dear Chief Judge Stark:
`I write on behalf of Defendants Apotex Corp. and Apotex Inc., (collectively, “Apotex”) in
`opposition to Plaintiff Bayer Healthcare LLC et al.’s (collectively, “Bayer”) letter to Your Honor
`regarding discovery relating to U.S. Patent No. 8,957,232 (the “’232 patent”). Apotex respectfully
`asks the Court to (1) deny Bayer’s request that the Court compel Apotex to produce unexpired
`samples of its ANDA product, and (2) deny Bayer’s request that the Court sever C.A. No. 18-1465
`(the “’232 Patent Case”) from C.A. No. 16-1221 (the “Main Case”) and stay the ’232 Patent Case
`until Apotex manufactures and produces to Bayer additional samples of its ANDA Product.
`A. Apotex Never Agreed to Produce Unexpired Samples of Its ANDA Product
`Apotex does not dispute Bayer’s recitation of the procedural history relating to the Main
`Case and portions of the ’232 Patent Case. Apotex, however, disagrees with Bayer’s
`understanding that “Apotex had ‘represented that Apotex can produce the samples requested in
`[Dov Grossman’s] August 29, 2018 letter to Ian Scott, with the caveat that Apotex no longer has
`unexpired samples of the regorafenib API.” D.I. 122 (Raucci letter at 2).
`Apotex informed Bayer at least as early as November 19, 2019 that its sample API was
`expired. See D.I. 122 (Ex. A at 5). As an accommodation to Bayer, Apotex agreed to purchase
`new unexpired API from its supplier and produced it to Bayer. See Ex. 1 at 1. When counsel for
`Apotex became aware that Apotex’s ANDA product expired in March, 2018 under the FDA’s
`Guidance for Industry ANDAs (two months before the ’232 patent issued) (see Ex. 2 at 3-4), we
`immediately informed counsel for Bayer. See D.I. 122 (Ex. A at 5). During a meet-and-confer on
`March 26, 2019, Apotex informed Bayer that it would send its ANDA product to Bayer’s experts,
`after which they were free to use the product in any way they saw fit. See Ex. 1 at 2 (confirming
`the March 26, 2019 meet-and-confer). Counsel for Bayer subsequently informed Apotex that it
`would not be testing the expired product. After Bayer finally provided Apotex with proper
`addresses, Apotex shipped both the unexpired API and expired ANDA product to Bayer’s
`respective experts. See Ex. 1 at 1. On April 12, 2019, Apotex again sought to accommodate Bayer
`by offering additional time to allow Bayer to test Apotex’s API and ANDA product. Id. at 1.
`Bayer responded by reiterating its unfounded understanding that Apotex would supply unexpired
`tablets and indicated that the “schedule for the ’232 patent depends on the resolution of that
`dispute.” Id. at 1.
`Apotex has never indicated, either implicitly or explicitly, that it would provide unexpired
`ANDA product to Bayer. Apotex has consistently maintained that it would provide Bayer with
`sample API and ANDA product “[t]o the extent possible,” and has diligently worked toward that
`end. See D.I. 122 (Ex. A at 5; see also id. at 7 (“To the extent possible and such information is
`under Apotex’s custody and control, Apotex will produce the samples requested by Bayer in your
`August 29, 2018 letter to Ian Scott, as well as the material data safety sheets and any handling and
`storage instructions, as well as the XRPDs requested in your August 29, 2018 letter to Ian Scott.”)).
`Bayer fails to provide any evidence to support its “understanding” that Apotex would produce
`unexpired ANDA product. This is because there is none.1
`
`
`1 In its letter to the Court, Bayer omitted Apotex’s response to Dov Grossman’s email of
`March 25, 2019 to Philip Kouyoumdjian, in which Mr. Kouyoumdjian requested that Bayer
`
`10907623/1
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`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 3 of 43 PageID #: 998
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`B. There is No Precedent to Compel Apotex to Make New ANDA Product
`Bayer does not cite, and Apotex is not aware of any case in which a court compelled a
`generic drug manufacturer to make new samples solely for purposes of litigation. Indeed, at least
`two courts have denied such a request, including this one. The Eastern District of Pennsylvania
`ruled that Fed. R. Civ. P. 34(a) does not compel production of items that are not “in the responding
`party’s possession, custody or control,” including products not currently manufactured, and thus
`not currently in the defendant’s possession. Apotex, Inc. v. Cephalon, Inc., Civ. No. 2:06-cv-2768,
`2010 WL 11463178 at *2 (E.D. Pa. April 9, 2010). More recently, this Court also held that it
`would not compel a generic drug company to produce unexpired ANDA product. See Ex. 4 (Wyeth
`LLC, et al. v. Alembic Pharmaceuticals, Ltd., et al., D. Del., C.A. No. 16-1305-RGA, Andrews, J.
`(Nov. 29, 2018) (Transcript). In Wyeth, et al. v. Alembic et al., Judge Andrews stated the
`following:
`So as I understand it, plaintiff wants some 100-milligram tablets, maybe some 500,
`too, and Sun doesn’t have any anymore, or any that are other than the expired ones
`that they gave. So they’ve got nothing to produce here, and I’m not going to make
`them make some more. And I’m also not going to make them stipulate that the
`expired tablets are representative of their ANDA product (emphasis added).
`Id. at 4:3-9.
`Similarly, Apotex has no unexpired sample tablets to produce. And, Apotex is not required
`to stipulate that its expired tablets are representative of its ANDA product. Accordingly, the Court
`should deny Bayer’s request that, unless Apotex agrees not to contest infringement, the Court
`should order Apotex to produce unexpired samples of its ANDA product.
`C. The ’232 Patent Case Should Not Be Severed from the Main Case
`Bayer fails to cite any authority to support its argument that the Court should sever the ’232
`Patent Case from the Main Case. This is because there is no precedent for such an order. In fact,
`the contrary is true. In one case where a defendant already had plans to manufacture new,
`unexpired samples, the court denied the production of those samples immediately after their
`planned manufacture, holding that the federal rules do not require production of responsive
`information immediately after it becomes available. Shionogi Pharma Inc. v. Mylan Inc., CA No.
`10-135 (D. Del. Aug. 13, 2012), slip op. at 2 (Ex. 5).
`The ’232 Patent Case and the Main Case, which were consolidated on December 28, 2018
`should not now be severed.
`D. Expired Samples May Be Used to Determine Noninfringement
`An expert may conclude that a defendant’s unexpired ANDA product may or may not
`infringe based on his or her testing of expired ANDA product. In Supernus Pharms., Inc. v. TWi
`Pharms., Inc., TWi challenged plaintiff’s expert, Dr. David Bugay, conclusion because he “‘tested
`expired samples of TWi’s product,’ which ‘calls the testing into question as it was not conducted
`on the actual product TWi will sell, because FDA regulations do not permit the sale of expired
`product.’” Supernus Pharms., Inc. v. TWi Pharms., Inc., 265 F. Supp. 3d 490, 509 (D.N.J. Sep.
`
`produce any evidence that Apotex had represented that it had unexpired samples of its ANDA
`product. Mr. Grossman did not provide any. See Ex. 3 at 1.
`
`10907623/1
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 4 of 43 PageID #: 999
`
`21, 2017). However, the Court ruled that since the TWi Tablets were only subject to a proposed
`expiration date—like Apotex’s in this case—there was no evidence that the TWi Tablet tested by
`Dr. Bugay was not representative of the TWi Tablets that TWi submitted to the FDA for approval
`and that TWi intended to market. The Court also held that there was no evidence that Dr. Bugay’s
`analysis was impaired, altered, or otherwise inaccurate because he tested a sample tablet beyond
`its proposed expiration date. See id. Dr. Bugay is acting as Bayer’s expert in the instant case, and
`is free to test the samples produced to him by Apotex.
`This Court has followed a similar procedure in determining whether expired samples are
`representative of unexpired samples. In Wyeth, et al. v. Alembic et al., supra, Judge Andrews
`allowed the plaintiff to test defendant’s expired product to determine infringement. He noted that
`if plaintiff’s and defendant’s experts differ in their conclusions, it then becomes “a fact question”
`for the Court. See Ex. 5 at 8:4-9:20. Judge Andrews then reiterated that plaintiff’s “got expired
`tablets. I’m not going to get you unexpired tablets, so you need to do what you need to do in order
`to make your best argument down the road.” Id. at 9:21-24. Bayer, therefore, is free to conduct
`its own testing on Apotex’s sample tablets, just as Apotex is free to challenge Bayer’s testing
`methods during expert discovery and at trial.
`E.
`
`F. Apotex Does Not Oppose Modifying the Scheduling Order
`Apotex will not object to pushing back the scheduling order to allow Bayer to conduct
`testing on Apotex’s API and ANDA product. However, after conducting fact discovery relating
`to the ’232 patent, Apotex has determined that many documents produced in connection with the
`’232 patent are related to both the ’553 and ’107 patents. Thus, if this Court agrees to modify the
`schedule for the ’232 Patent Case, Apotex requests that the remaining deadlines for the Main Case
`be similarly adjusted in order to give it the opportunity to take further discovery on the ’553 and
`’107 patents based on 2 new discovery in connection with the ’232 patent.
`
`Respectfully,
`
`/s/ Kenneth L. Dorsney
`
`Kenneth L. Dorsney (#3726)
`
`cc:
`
`all counsel of record via efiling and email service
`
`10907623/1
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 5 of 43 PageID #: 1000
`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 5 of 43 PageID #: 1000
`
`Exhibit 1
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 6 of 43 PageID #: 1001
`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 6 of 43 PagelD #: 1001
`
`Kouxoumdiian. Philip Y.
`
`From:
`
`Sent:
`
`To:
`Cc:
`
`Grossman, Dov <DGrossman©wccom>
`
`Friday, April 12, 2019 10:36 AM
`
`Kouyoumdjian, Philip Y.
`Genderson, Bruce; Perlman, Adam; Bowers, Seth; Picozzi. Ben; Scott, Ian;
`
`dfahnestock©mnat.com; Raucci, Anthony D.; KDorsney@morrisjames.com
`
`Subject:
`
`RE: Bayer v. Apotex, CA. 16—1221-LPS
`
`Phil,
`
`Our understanding is that you have produced expired samples of Apotex’s product—not the unexpired samples that We
`
`requested and that we understood you were going to provide. The production of unexpired samples is the issue
`
`involved in the discovery dispute currently pending before the Court. The schedule for the ’232 patent depends on
`resolution of that dispute.
`
`Regards,
`Dov
`
`From: Kouyoumdjian, Philip Y. [mailto:pkouyoumdjian@taftlaw.com]
`
`Sent: Friday, April 12, 2019 10:28 AM
`To: Grossma n, Dov <DGrossman@wc.com>
`
`Cc: Genderson, Bruce <BGenderson @wc.com>; Perlman, Adam <APer|man@wc.com>; Bowers, Seth
`<SBowers@wc.com>; Picozzi, Ben <BPicozzi@wc.com>; Scott, Ian <iscott@taftlaw.com>; dfahnestock@mnat.com;
`Ra ucci, Anthony D. <araucci@mnat.com>; KDorsney@morrisjames.com
`
`Subject: Re: Bayer v. Apotex, (LA. 16—1221—LPS
`
`Dov,
`
`In light of the fact that your experts have received Apotex’s sample API and product, please let us know how much time
`you need to complete fact discovery with respect to the {232 patent. We will provide you with dates for the depositions
`of Tom Hu and Sandeep Patel shortly.
`
`Best,
`Phil
`
`Taft I
`
`Philip Y. Kouyoumdjian/ Partner
`Taft Stettinius 8!. Hollister LLP
`14 Penn Plaza
`
`225 West 34th Street
`
`Suite 2102
`
`New York NY 10122
`Direct: 917.534.7180
`
`www.taft|aw.com / pkouyoumdjian@taftlaw.coin
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 7 of 43 PageID #: 1002
`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 7 of 43 PagelD #: 1002
`
`
`111 East Waclter Drive 0 Suite 2800 Chicago, IL 60601
`Direct: 312.836.4026 0 Fax: 312.966.8555
`
`Subscribe to our law updates
`
`This message may contain information that is attorney-client privileged, attorney work product or otherwise
`
`confidential. If you are not an intended recipient, use and disclosure of this message are prohibited. If you received this
`
`transmission in error, please notify the sender by reply e-mail and delete the message and any attachments.
`
`On Apr 11, 2019, at 5:32 AM, Grossman, Dov <DG rossman@wc.com> wrote:
`
`Phil,
`
`i write to follow up concerning the status of discovery regarding the ’232 patent and the schedule.
`
`As you know, we offered dates for both Birgit Keil and Alfons Grunenberg during the discovery period,
`but for various reasons (which i do not intend to debate here) those depositions did not happen. We
`are looking into new dates for those witnesses and will get back to you.
`I note that we requested
`depositions of Shui Sheng and Sandeep Patel, but still have not received dates from you for those
`witnesses. Please let us know when they are available.
`
`Also, as we discussed on the parties’ meet-a nd-confer call on March 26, 2019, given the ongoing
`discovery dispute the parties anticipate that the schedule for the ’232 patent will need to be
`
`adjusted. We agreed, however, that the schedule for the ’553 and ’107 patent would remain as is.
`
`Regards,
`Dov
`
`Dov P. Grossman
`
`Williams 8: Connolly LLP
`
`725 TWelfth St., N.W., Washington, DC 20005
`
`{P} 202—434-5812 | (F) 202-434-5029
`
`dgrossmaanc.com | www.wc.com[dgrossman
`
`This message and any attachments are intended only for the addressee and may contain information that is
`privileged and confidential. If you have received this message in error, please do not read, use, copy, distribute, or
`disclose the contents of the message and any attachments. Instead, please delete the message and any
`attachments and notify the sender immediately. Thank you.
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 8 of 43 PageID #: 1003
`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 8 of 43 PageID #: 1003
`
`Exhibit 2
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 9 of 43 PageID #: 1004
`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 9 of 43 PageID #: 1004
`
`Guidance for Industry
`ANDAs: Stability Testing of
`Drug Substances and Products
`
`Questions and Answers
`
`U.S. Department of Health and Human Services
`Fond and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`May 2014
`Generics
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 10 of 43 PageID #: 1005
`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 10 of 43 PageID #: 1005
`
`Guidance for Industry
`ANDAs: Stability Testing of
`Drug Substances and Products
`
`Questions and Answers
`
`Additiona! copies are arrait'abz'efi‘om:
`Office of Communications
`Division ofDr-ng Information, W05 I, Room 2201'
`Centerfor Drug Evaluation and Research
`Food and Drug Administration
`.1 0903 New Hampshire Ave, Siiver Spring, MD 20993
`Phone: 30f-796—3400; Fax: 30f-847—87M
`cfi'ngngfo@fdn.hns.gov
`
`(JV/Dru sx’Gm'danceC‘om)It'mtceRe m'morvfnfin'nration/Ctridoneex-“definrk.hm:
`
`Int).'x?’um'1t'_ do.
`
`US. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research (CDER)
`
`May 2014
`Generics
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 11 of 43 PageID #: 1006
`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 11 of 43 PageID #: 1006
`
`TABLE OF CONTENTS
`
`I.
`
`II.
`
`INTRODUCTION............................................................................................................. 1
`
`QUESTIONS AND ANSWERS ....................................................................................... 1
`
`A. General ............................................................................................................................................ 1
`
`B. Drug Master File ............................................................................................................................ 5
`
`C. Drug Product Manufacturing and Packaging ............................................................................. 6
`
`D. Amendments to Pending ANDA Application ............................................................................ 12
`
`E.
`
`Stability Studies ............................................................................................................................ l3
`
`

`

`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 12 of 43 PageID #: 1007
`Case 1:16-cv-01221-LPS Document 126 Filed 05/02/19 Page 12 of 43 PageID #: 1007
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`Contains Nonbinding Recommendations
`
`Guidance for Industry1
`ANDAs: Stability Testing of Drug Substances and Products
`Questions and Answers
`
`This guidance represents the Food and Drug Administration‘s (FDA’s) current thinking on this topic. It
`does not create or confer any rights for or on any person and does not operate to bind FDA or the public.
`You can use an alternative approach if the approach satisfies the requirements of the applicable statutes
`and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for
`implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate
`
`number listed on the title page ofthis guidance.
`
`I.
`
`INTRODUCTION
`
`This guidance provides answers to questions from the public comments we received on the drafi'
`guidance for industry on AND/Is: Stability Testing ofDrug Substances and Products2 (FDA
`stability guidance) that published in the Federal Register of September 25, 2012. The final
`guidance for industry of the same title published in the Federal Register of June 20, 2013.
`Comments received on the draft ofthis guidance published in the Federal Register of August 27,
`2013 have also been incorporated. General iSSues; drug master tiles (DMFs); drug product
`manufacturing and packaging; and stability studies are discussed in this guidance and are
`intended to clarify the stability testing data recommendations for abbreviated new drug
`applications (ANDAs). In this document, the terms drug substance and active pharmaceutical
`ingredient (API) are used interchangeably.
`
`FDA’s guidance documents, including this guidance, do not establish legally enforceable
`responsibilities.
`instead, guidances describe the Agency’s current thinking on a topic and should
`be viewed only as recommendations, unless specific regulatory or statutory requirements are
`cited. The use of the word should in Agency guidances means that something is suggested or
`recommended, but not required.
`
`II.
`
`QUESTIONS AND ANSWERS
`
`A.
`
`General
`
`Q1: What is the scope ofamt‘ impiementation datefor the FDA stability guidance?
`
`A1:
`
`The FDA stability guidance covers all new ANDAs under the Federal Food,
`Drug, and Cosmetic Act, section 505 (j), and DMFS (Type I]. for drug
`
`1 This guidance has been prepared by the Office ofGeneric Drugs and Office of Pharmaceutical Science in the
`Center for Drug Evaluation and Research (CDER) at the Food and Drug Administration.
`2 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA
`Drugs guidance Web page at
`http:iiwwwfdagoviDrugsiGuidanceComplianceRegulatoryInformationiGuidancesidefaulthtm.
`
`

`

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`Contains Nonbinding Recommendations
`
`substances that support the ANDAS). It does not apply to postapproval
`changes.
`
`The implementation date is June 20, 2014.
`
`Q2:
`
`How wiii it: is guidance affect the President ’3' Emergency Plan for AIDS Relief
`(PEPFAR) andpositron emission tomography (PET) ANDAS?
`
`A2:
`
`For chemistry, manufacturing, and controls (CMC) information, PEPFAR
`ANDAS should follow the guidance for industry on Fixed Dose
`Combinations, (To-Packaged Dmg Products, and Single-Entity Versions of
`Previously Approved Antiretroviroisfor the Treatment oinV. 3
`
`For PET ANDAs, the Agency recommends a minimum of three batches at or
`near the upper end of the proposed radio-concentration. If different
`synthesizers (methods of synthesis) are used, three batches from each method
`of synthesis at or near the upper end of the proposed radio-concentration are
`recommended. Batches do not have to be made in the same facility. For any
`additional manufacturing facilities, applicants should provide stability data on
`at least one batch at or near the upper end of the proposed radio-concentration
`from each facility, although bracketing approaches may be submitted for
`review. For additional information, the Agency has published a guidance for
`industry on FDA Oversight ofPET Products, Questions and Answers.4
`
`Q3(1): Can an ANDA be submitted with 6 months ofaccelerated stability and 6 months of
`tong-term stability data?
`
`A3(i):
`
`Yes. An ANDA applicant should submit 6 months of accelerated stability
`data and 6 months of long-term stability data at the time of submission.
`However, if 6 months of accelerated data show a significant change5 or failure
`of any attribute, the applicant should also submit 6 months of intermediate
`data at the time of submission.
`
`Q3031): When do intermediate stability studies need to be initiated in the event offailure at
`accelerated condition ?
`
`A3(ii):
`
`An ANDA applicant should start accelerated, intermediate, and long-term
`stability studies at the same time so the data are available at the time of
`submission if the accelerated stability study fails.
`
`3 See footnote 2.
`4 Ibid.
`5 See the International Conference on Harmonisation (ICH) guidance to industry on QiA(R2) Stabiiity Testing
`of New Drag Substances and Products, section 2.2.7.1 .
`
`

`

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`Contains Nonbinding Recommendations
`
`Q3(iii): ifone among the three batches in accelerated conditions shows a significant
`change, what should be done?
`
`A3(iii):
`
`If accelerated data show a significant change or failure of any attribute in one
`or more batches, an applicant should submit intermediate data for all three
`batches. In addition, the submission should contain a failure analysis (i.e.,
`discussion concerning the observed failure(s)).
`
`Q4:
`
`Can stability bracketing and/or matrixing be used to determine the packaging
`configurations to be placed on stability for an original ANDA withont prior approval
`from the Office of Generic Drugs (OGD)?
`
`A4:
`
`Yes. You should follow the Intemational Conference on Harmonisation (ICH)
`guidance for industry on Q?D Bracketing and Molrixing Deszgnsfor Stability
`Testing ofNew Drug Substances and Products6 and its example tables.
`
`Q5(1'): Ifan application that qualifiesfor the Generic Drug User Fee Act (GD UFA) 10-month
`review isfiled with 6 months ofaccelerated and 6 months oflong-term data, and there
`are no blocking patents or exclusivities, will 24 months ofshelf life be granted?
`
`Q5(ii): During the review cycle, will the application need to be updated with 12 months of
`long-term data?
`
`A5(i,ii):
`
`FDA willgrant a shelf life period of two times the available long--term data at
`the time of approval (up to 24 months) following the iecommendation of the
`ICi-I QIE Evaluation ofSlabiiity Data (ICH QlE) guidance? provided the
`submitted data are satisfactory, and data evaluation and appropriate
`commitments are provided in accordance with [CH Q1 E. Please refer to the
`decision tree (Appendix A) in ICH QlE. The ANDA should be updated with
`12 months of long-term data during the review cycle.
`
`Q6:
`
`Can only two lots offinished product at pilot scale batch size ever be considered
`sufficient to support the stability ofan ANDA for simple dosageforms?
`
`A6:
`
`According to the FDA stability guidance, the applicant should submit data
`from three pilot scale batches or should submit data from two pilot scale
`batches and one small scale batch. This applies to all dosage forms. If the size
`of the pilot scale batch does not follow ICH recommendations, the applicant
`should provide ajustification. See also section C, question 20 for additional
`information regarding exceptions.
`
`6 See footnote 2.
`7 Ibid.
`
`

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`Contains Nonbinding Recommendations
`
`How is the proposed shelflife supposed to be calculated? Will 6 months of accelerated
`data equal 24 months at long-term?
`
`A7:
`
`[CH QlE principles will help in the calculation of shelf life. Data from the
`three ANDA submission batches (i.e., 6 months), accelerated data meeting all
`criteria (without significant change per ICH QlA(R2))= and 12 months long-
`term data without variability will not need statistical evaluation, and with
`apprOpriate post approval stability commitments, can be used to support
`extrapolation to a 24 months shelf life.
`
`If there is a signifi cant change in the accelerated data, [CH Q1 E, Appendix A,
`provides more details regarding when intermediate condition stability data are
`recommended.
`
`Q8:
`
`Will the recommendation for 6 months accelerated data be met by providing 24 weeks
`ofdata as 12 weeks is typically accepted as equivalent to 3 months?
`
`A8:
`
`No. FDA, following the recommendations of ICH stability guidances refers
`to timefrarnes in terms of months and not weeks.
`
`Q9:
`
`When a patent is due to shortly expire and there are no approved ANDAs, can wefile
`with 3 months stability data with a commitment to supply 6 months data when
`available?
`
`A9:
`
`No. Data recommendations in the FDA stability guidance should be followed
`irreSpective of patent status.
`
`Q10: How long do the three pilot scale batches, submitted as a part ofan ANDA, need to be
`stored before destruction ?
`
`A10:
`
`Sample storage times are discussed in 21 CFR 320.38 and 21 CFR 320.63 in
`connection with bioequivalence study samples. In general, ANDA
`submission batch samples should be stored for 1 year after approval of the
`ANDA, and samples of the drug product used for bioequivalence studies must
`be stored following the requirements listed in 21 CFR 320.38 and 21 CFR
`320.63. In addition, the guidance for industry on Handling and Retention of
`BA and BE Testing Sampless may be helpful regarding the procedure for
`handling reserve samples from relevant bioavailability and bioequivalence
`studies. Additional information on sample quantities (for retention purposes)
`is discussed in 21 CFR 211.170 (a) and (b), Reserve Samples.
`
`8 See footnote 2.
`
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`Contains Nonbinding Recommendations
`
`B.
`
`Drug Master File
`
`Q1:
`
`Please clarify the effect ofthe FDA stability guidance on Drug Master File (DMF)
`holders.
`
`Q](i): How many months ofiong-term and accelerated data are required when a
`“Completeness Assessment” is performed on the DMF? Also, what shonid the DMF
`stability section contain for a Compieteness Assessment?
`
`A1 (i):
`
`To pass the Completeness Assessment, DMFs should include the stability
`protocol, commitments, and data demonstrating that stability studies have
`started. The initial and one additional time point for the accelerated studies
`and long-term studies are sufficient. If the DMF does not meet the
`recommendations under A] (ii) below at the time of the Completeness
`Assessment the DMF holder should amend the DMF with updated stability
`data to prepare for full scientific review.
`
`Qt (it): Are stabiiity datafrom three current good man ufacturing practice (CGMP) batches
`required to befiied in the DMF to support the API retest date? Aiso, how many months
`ofiong—term and acceierated data are requiredfor pilot scaie batch es?
`
`Al(ii):
`
`Yes. Per ICH Q1A(R2) data from formal stability studies should be provided
`on at least three primary batches9 and the batches should be manufactured to a
`minimum of pilot scale10 for the drug substance to be filed in the DMF. These
`batches should be made under CGMPs. The FDA stability guidance
`recommends 6 months of accelerated data and 6 months of long-term data for
`the pilot scale batches to be submitted for a full scientific review of the DMF.
`Additional long-term data for all three batches, as the data becomes available
`through the proposed retest period, should be submitted as an amendment.
`
`Q2: Wiii submissions to DMFs be accepted based on stability datafrom production scaie
`batches?
`
`A2:
`
`Yes. Per ICH Q1A(R2), section 11, A, 8, Stability Commitment (2.1.8), the
`submission is appropriate if satisfactory stabiiity data from at least three
`production batches made under CGMP are filed in the DMF with 6 months of
`accelerated data and data for samples stored under long-term conditions that
`cover the proposed retest period.
`
`Q3:
`
`Should executed batch recordsfor the three batches be included in the DMF
`submission ?
`
`A3:
`
`One representative executed batch record will be sufficient.
`
`9 “Primary batch” is defined in I CH Q 1A(R2) Glossary.
`“3 See ICH Q1A(R2) Glossary.
`
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`Contains Nonbinding Recommendations
`
`C.
`
`Drug Product Manufacturing and Packaging
`
`Q1:
`
`Can the split bulk solution fitted into differentfih.‘ volumes he considered discrete
`batches?
`
`A1:
`
`To be consistent with [CH Ql A(R2), we recommend that discrete finished
`product batches be produced that represent different batches of bulk solution.
`Split filling one batch of bulk solution into different fill volume sizes would
`not constitute discrete batches.
`
`Q2:
`
`Can you clarify the packaging recommendationsfor the submission batchesfor blow-
`fill—seal containers?
`
`A2:
`
`Blow-fill-seal containers are not an exception from regular packaging and are
`usually packaged inside a secondary container or a carton. The secondary
`packaging should be included in all three batches. ICH QIA(R2) addresses
`secondary packaging usefulness (see section II, B, 4, Drug Product Container
`Closure System (22.4)).
`
`Q3 -'
`
`Should at! three batches be stored in final pr0posed packaging?
`
`A3:
`
`Yes. You should package all three batches in the container closure system
`proposed for marketing. ICH Q1A(R2) addresses this question (see section [1,
`B, 4, Drug Product Container Closure System (22.4)).
`
`Q4:
`
`What is the Agency is position on using different lots ofAPIs and/or packaging
`materiais? How many API lots should be used in the manufacture offinishedproduct
`tots used to support the ANDA ?
`
`A4:
`
`It is not necessary to use different lots of packaging material, except in cases
`where the packaging material could affect drug product performance andicr
`delivery. A minimum of two lots of the drug substance should be used to
`prepare the three primary batches of drug product. 1'
`
`Q5:
`
`Should the smah‘ scale batches be packaged with commercial equipment? Also, is it
`acceptable to package using research equipment or by hand?
`
`A5:
`
`Yes. Small scale batches should be packaged with commercial equipment, or
`the packaging equipment should be similar to that preposed for use prior to
`market distribution. No, it is not recommended to package small scale batches
`using research equipment or by hand. Please refer to [CH Q1A(R2) section Ii,
`B, 3, Selection of Batches (2.2.3) and the glossary definition for primary
`batches.
`
`'1 For nasal aerosols and nasal sprays, you should use three different lots of drug substance.
`
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`Contains Nonbinding Recommendations
`
`Q6:
`
`What will the recommendation for secondary packaging be?
`
`A6:
`
`We recommend following ICH QIA(R2) section It, B, 4, Drug Product
`Container Closure