UNITED STATES PATENT AND TRADEMARK OFFICE
`
`———————
`
`BEFORE THE PATENT TRIAL AND APPEAL BOARD
`
`———————
`
`ETON PHARMACEUTICALS, INC.,
`
`Petitioner
`
`v.
`
`EXELA PHARMA SCIENCES, LLC,
`
`Patent Owner
`
`———————
`
`U.S. PATENT NO. 10,478,453
`
`DECLARATION OF HARRY “WARREN” JOHNSON
`
`
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`Eton Ex. 1022
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`1.
`
`My name is Harry “Warren” Johnson. I am over 21 years of age. I
`
`submit this declaration on behalf of Eton Pharmaceuticals, Inc. (hereinafter “Eton”)
`
`in connection with the above-captioned matter. I am not being compensated for my
`
`time, although, as noted below, I have an indirect, potential financial interest in this
`
`matter.
`
`2.
`
`In connection with this Declaration, I reviewed select business records
`
`of Allergy Laboratories, Inc. (hereinafter “Allergy Labs”) and AL Pharma, Inc.
`
`(hereinafter “AL Pharma”). These records were created and maintained in the
`
`ordinary course of Allergy’s and AL Pharma’s business.
`
`3.
`
`I also held discussions with several individuals who provided
`
`information that I also relied upon in preparing this Declaration.
`
`4.
`
`Based on my personal knowledge and the results of my investigation, I
`
`am informed and understand that the facts stated in this Declaration are true.
`
`Background
`
`5.
`
`From January 2001 to approximately January 2017, I served as Vice
`
`President and was a 49% owner of Allergy Labs. My wife owned the remaining
`
`shares. In or around January 2017, Allergy Labs sold some of its assets and business
`
`activities, including the Allergy Laboratories name, to ALK. Allergy Labs (which
`
`changed its name to AL Pharma, Inc. (“AL Pharma”) following the sale) retained
`
`the real estate, including its Oklahoma City plant, and the cysteine products, which,
`
`2
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`as discussed below, Allergy Labs previously manufactured for Sandoz Inc.
`
`(“Sandoz”). ALK currently leases AL Pharma’s Oklahoma City plant. My wife and
`
`I own all outstanding shares of AL Pharma. I have served as Vice President of AL
`
`Pharma since January 2017.
`
`6.
`
`AL Pharma has a profit sharing arrangement with Eton in connection
`
`with Eton’s proposed L-Cysteine Hydrochloride Injection drug product that is the
`
`subject of Eton’s Abbreviated New Drug Application (ANDA). I understand that
`
`Eton’s ANDA has prompted a suit for alleged patent infringement by Exela Pharma
`
`Sciences, LLC (“Exela”). I am advised that Exela contends the manufacture, use
`
`and/or sale of Eton’s proposed ANDA product would infringe one or more claims
`
`of U.S. Patent Nos. 10,478,453 and 10,583,155.
`
`The Sandoz L-Cysteine Product
`
`7.
`
`In addition to serving as Vice President, my job responsibilities at
`
`Allergy Labs during the time frame of January 2001 through January 2017 included
`
`manufacturing, sales, accounting, inventory and purchasing. My wife, a chemist and
`
`pharmacist, was primarily responsible for quality assurance and quality control.
`
`8.
`
`Prior to approximately 2008, Allergy Labs contract-manufactured an
`
`L-Cysteine Hydrochloride Injection, USP drug product for Parenta Pharmaceuticals
`
`(“Parenta”). Allergy Labs manufactured the Parenta L-Cysteine Product at
`
`Allergy’s manufacturing plant in Oklahoma City, Oklahoma. In or about 2008, I
`
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`understand that Parenta products were acquired by Sandoz. From that time until
`
`2016, Allergy Labs contract-manufactured the L-Cysteine Hydrochloride Injection
`
`Product (50 mg/mL product and available in both single dose vials and pharmacy
`
`bulk package) for Sandoz (the “Sandoz L-Cysteine Product”).
`
`9.
`
`Allergy Labs contract-manufactured the Sandoz L-Cysteine Product
`
`pursuant to Sandoz’s specifications and sold the finished product to Sandoz pursuant
`
`to purchase orders.
`
`10.
`
`Pursuant to its agreement with Sandoz, various regulatory obligations,
`
`and as part of its ordinary business practices, Allergy Labs made and kept records
`
`associated with its manufacture of the Sandoz L-Cysteine Product. These records
`
`included, but were not limited to, batch records for each lot of Sandoz L-Cysteine
`
`Product that Allergy Labs manufactured for Sandoz.
`
`11. A true and correct copy of an exemplary batch record is attached as
`
`Exhibit A. This batch record is for lot #2072115 of the Sandoz L-Cysteine Product,
`
`which was manufactured on July 21, 2015. Batch records were made at or near the
`
`time of the events recorded therein by technicians who had training and knowledge
`
`and were responsible for making a record of the manufacturing process. It was
`
`Allergy Labs’ regular practice to create batch records like that attached as Exhibit
`
`A, and such batch records were created and kept in the ordinary course of Allergy
`
`Labs’ business. As was Allergy’s practice at the time, the date on which the product
`
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`was manufactured is reflected by the lot number assigned to the product. Consistent
`
`with that practice, the numbers in the lot # that I have shown in bold represent the
`
`manufacture date (#2072115) of 07/21/15 and the “2” stands for manufacturing line
`
`2 at the Oklahoma City plant.
`
`12.
`
` The batch record for lot #2072115 includes, among other things, the
`
`following forms: a “Lot Release Approval for Customer” (see pp.13-16), a “Cysteine
`
`Batch Manufacturing Record” (see pp.19-25), a “50 mL Cysteine HCl Injection Vial
`
`Manufacturing Record” (see pp.26-35), a “Filled Vial Labeling Record” (see pp.46-
`
`50), a “Printed Container (Carton) Packaging Record” (see pp.51-52), a “Package
`
`Insert Record” (see p.56) (which includes a true and correct copy of the package
`
`insert for the Sandoz L-Cysteine Product (see pp.53-55)), a “Sandoz Shipping Label
`
`Record – 50 mL Cysteine” (see pp.57-58), a “Particulate Matter Test” (see p.63),
`
`and a “Certificate of Analysis” from a third-party contract laboratory KABS (see
`
`p.68). The Certificate of Analysis (COA) from KABS contains, among other things,
`
`the aluminum and heavy metals content of the final product. As noted on the KABS
`
`COA, the aluminum level was measured by another third-party laboratory, Metrics
`
`Inc., of Greenville, North Carolina. The KABS COA for lot #2072115 reports 17
`
`ppb of aluminum for the sample tested by Metrics.
`
`13. Attached as Exhibit B is a collection of true and correct copies of
`
`KABS COAs corresponding to lots #2012114, 2012214, 2072115, 2072215,
`
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`2081915, 2082015, 2082115, 2093015, 2100115, and 2100215. In connection with
`
`its manufacture of the Sandoz L-Cysteine Product, it was Allergy Labs’ practice to
`
`have KABS analyze samples for every commercial batch of Sandoz L-Cysteine
`
`Product prior to the commercial release. As part of that practice, Allergy Labs would
`
`receive and maintain KABS COAs of the type included in Exhibit B. The KABS
`
`COAs were maintained in the ordinary course of Allergy Labs’ business.
`
`14.
`
`Pursuant to Allergy Labs’ ordinary business practices, the data from the
`
`KAB COAs was included along with other data in a COA bearing the Allergy Labs
`
`letterhead. Attached as Exhibit C are true and correct copies of the Allergy Labs
`
`COAs that correspond to the KABS COAs of Exhibit B, namely Allergy Labs COAs
`
`for lots #2012114, 2012214, 2072115, 2072215, 2081915, 2082015, 2082115,
`
`2093015, 2100115, and 2100215. It was Allergy Labs’ practice, consistent with
`
`what I understand to be required for pharmaceuticals manufactured and distributed
`
`commercially, to generate a COA on Allergy Labs letterhead for each commercial
`
`batch of Sandoz L-Cysteine Product to assure that these products met agreed upon
`
`drug release specifications for potency and impurities. It was Allergy Labs’ regular
`
`practice to create Allergy Labs COAs like those attached as Exhibit C, and such
`
`COAs were created and kept in the ordinary course of Allergy Lab’s business.
`
`15. Consistent with the aluminum levels reported in the COAs attached as
`
`Exhibits B and C, respectively, the aluminum levels initially measured in the Sandoz
`
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`L-Cysteine Products (i.e., within several weeks of manufacture) were typically
`
`below about 100 ppb. Based upon stability studies of the Sandoz L-Cysteine
`
`Product, we at Allergy Labs understood that aluminum levels would increase to
`
`several hundred ppb after storage for approximately 1-24 months but remained
`
`substantially below the NMT 5,000 ppb of aluminum noted on the label of the
`
`Sandoz L-Cysteine Product. As we believed at the time, the likely source of the
`
`aluminum detected in the Sandoz L-Cysteine Product samples was aluminum
`
`leached from the glass vials in which the Sandoz L-Cysteine Product was packaged.
`
`16. With respect to the manufacture of the Sandoz L-Cysteine Product,
`
`Allergy Labs followed materially the same manufacturing process from 2010 until
`
`2016, which is materially the same as the process previously followed by Allergy
`
`Labs for the Parenta L-Cysteine Product since 2003. The process set forth in the
`
`“Cysteine Batch Manufacturing Record” for lot #2072115 (see Exhibit A) is
`
`representative of the process by which the Sandoz L-Cysteine Product was
`
`manufactured, and included the following steps, among others:
`
`a. Stirring water for injection, USP (WFI) in a vessel at temperature
`
`not more than (NMT) about 60 C (see p.22 at steps 4-6 (“Allow WFI
`
`to cool between the temperature of 20C-32C” and “Insert the mixer
`
`into the WFI . . . . Turn on the mixer and set the mixer speed at 250
`
`+/- 10 rpms”));
`
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`b. Allowing the vessel to cool to a temperature of NMT 30 C (see p.22
`
`at steps 4-6);
`
`c. Contacting the WFI with L-Cysteine Hydrochloride, Monohydrate,
`
`USP (L-Cysteine) for not longer than (NLT) 15 minutes (see p.23 at
`
`step 9 (“With mixing, add . . . Cysteine HCl Monohydrate (item 02)
`
`and mix for 5-10 minutes”));
`
`d. Adjusting the pH with concentrated Hydrochloric Acid, NF and/or
`
`5.0N Sodium Hydroxide, NF (see pp.23-24 at steps 11-12 (Remove
`
`sample, measure and record pH, “specification of 1.20-1.30”); the
`
`Allergy Labs process had hydrochloric acid and sodium hydroxide
`
`readily available for adjusting pH should it be needed (see p.20));
`
`e. Mixing for a minimum of about 10 minutes (see p.25 at step 14
`
`(“Mix for 15 +/- 5 minutes”))
`
`f. Capping the vessel and allowing to stand (see p.25 at step 19 (“Close
`
`the lid on the tank”);
`
`g. Filling said mixture into container of use (see pp.24-25 at Vial
`
`Manufacturing Record, steps 13-16 (“Proceed with filing and
`
`stoppering of the vials”);
`
`h. Reducing the head space oxygen in said containers of use (see p.25
`
`at Vial Manufacturing Record, step 17 (“Nitrogen purging Aero
`
`8
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`50”)); and
`
`i. Sealing said containers of use (see p.25 at Vial Manufacturing
`
`Record, steps 18-19 (“Perform vial capping on all filled and
`
`stoppered vials”).
`
`17. Allergy Labs was also responsible for labeling, packaging, and
`
`shipping the finished Sandoz L-Cysteine 50 mg/mL Product. Allergy labeled the
`
`filled vials and placed a package insert in each carton. (see pp.34-35 at Vial
`
`Manufacturing Record, steps 28, 31-38). True and correct copies of the label and
`
`package insert are included in the batch record of Exhibit A.
`
`18. Allergy Labs followed the above-referenced manufacturing process for
`
`the Sandoz L-Cysteine Product in the ordinary course of Allergy Labs’ business and
`
`the process was generally known by Allergy Labs personnel. Allergy Labs also did
`
`not take any overt efforts to conceal the manufacturing process for the Sandoz L-
`
`Cysteine Product.
`
`AL Pharma NDA
`
`19.
`
`In or about January 2018, AL Pharma filed a New Drug Application
`
`No. 209649 (the “AL Pharma NDA”) with the United States Food & Drug
`
`Administration (FDA) for 5% L-Cysteine Hydrochloride Injection, USP, via the
`
`505(b)(2) regulatory pathway, a product which was intended for the same indications
`
`as a previously FDA-approved product, 7.25% Cysteine HCl Injection, USP (NDA
`
`9
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`
`
`019523; Hospira).
`
`20.
`
`The
`
`Proposed
`
`Finished
`
`Product Release
`
`Specifications
`
`(“Specifications”) for the 5% L-Cysteine HCl Injection, USP, recited, among other
`
`things, an Aluminum Content of not more than (NMT) 5,000 ppb and NMT 2.0%
`
`Cystine.
`
`21. With respect to the aluminum content of AL Pharma’s proposed
`
`specifications, by e-mail dated March 9, 2018 (a true and correct copy of which is
`
`attached as Exhibit D) the FDA advised AL Pharma that:
`
`The drug product L-Cy[s]teine Hydrochloride Injection is a small volume
`parenteral drug product used in TPN. Based on our previous experience with
`small volume parenteral drug products intended for addition to the TPN, we
`have determined that the aluminum dose delivered by your drug product, 5%
`L-Cysteine Hydrochloride Injection, USP, should be limited to (cid:148)0.6
`mcg/kg/day. To comply with this limit, the aluminum content in the final drug
`product should be controlled to (cid:148)350 mcg/L. This calculation is based on the
`clinical dose of 15 mg cysteine free base per gram of amino acid per day.
`Therefore, the proposed acceptance limit for the aluminum content in the
`finished drug product specification (3.2.P.5.1) must be revised to (cid:148)350 mcg/L.
`The drug product registration batches manufactured at OKC Allergy Supplies,
`Oklahoma City, OK have not been shown to meet the required acceptance
`limit for aluminum content.
`22.
`In response, AL Pharma amended the aluminum specification to (cid:148)350
`
`mcg/L ((cid:148)350 ppb) and submitted additional information demonstrating compliance
`
`10
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`

`

`with the FDA‘s proposed acceptance limit for aluminum content.
`
`23.
`
`I hereby declare under penalty of perjury under the laws of the United
`
`States of America that the foregoing is true and correct, and that all statements made
`
`of my own knowledge are true and that all statements made on information and belief
`
`are believed to be true. I understand that willful false statements are punishable by
`
`fine or imprisonment or both. See 18 U.S.C. § 1001.
`
`Date: flST/fijD-go
`
`Respectfully submitted,
`
`
`
`l
`
`l
`
`Eton Ex. 1022
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`
`Eton Ex. 1022
`11 of 131
`
`

`

`Exhibit A
`
`Exhibit A
`
`Eton Ex. 1022
`12 of 131
`
`Eton Ex. 1022
`12 of 131
`
`

`

`~-W~ O!!v 1:;i-16
`
`~ b?$ -l~ -I\
`
`QA Reviewed and Approved By/Date:
`
`Manufacturing Checklist Completed By/Date:
`
`1vo-d/-s-/o'l-l'>-•f\
`
`I Tunnel report reviewed by manufacturing (Line 2) Completed and Approved by QA (Qi ila sill! C1111H1Be11e Ge bol~ ;i.-. 01[-, ).• IS"
`Dry heat depyrogenating oven chart reviewed by manufacturing (Line I) Completed and Approved by QA (On file with Document Control)
`FAE-026-01 "Daily Autoclave Log• Equipment ID# 0237 and# 0238" (Line 2) Completed and Approved by QA (On file with Document Control)
`FAE-016-01 "Daily Autoclave Log -Equipment ID# 0002" (Line 1) Completed and Approved by QA (On file with Document Control)
`MFG-0S7-24 "Calculation of Percent Yields for Bulle Solution and Final Containers of Sterile Drug Products"
`I Fonn #:
`Sandoz Shipping Label Record
`P AL-002-08 "Package Insert Record"
`PAL-002-07 "Printed Container (Carton) Packaging Record"
`PAL-002-01 "Filled Vial Labeling Record"
`MFG-040-01 "Quarantine of Unlabeled Vials for Future Labeling Operations Fonn"
`QC-090-01 "AQL Vial Inspection" completed and approved by QC
`MFG-036-01 "Filled Vial Insp_ection Record"
`FAE-033-01 "Volume Verification Record-Line 2"
`F AE-017-01 "Volume Verification Record-Line 1"
`MFG-048-01 "Filling/Stoppering and Capping Line Clearance Record
`Vial Manufacturing Record completed and approved by the Prod. Supervisor
`Batch Manufacturing Record completed and approved by the Prod. Supervisor
`QA-006-02 "Corrective Interventio11_Log • Line l _~ Aseptic Products" completed and approved by QA
`Routine Intervention Log completed and approved by QA
`
`I Fonn #: V M f!.. -b/ 4
`I Fonn #: f,M. ;?_ ~ O I 0
`
`I Fonn #:
`
`Comments (Reference any Deviations, OOS, or CAPA Investigations in the Investigations section [page 3)):
`
`N/A
`
`FonnE~1\1f1b 6 2015
`Fonn Issue D,tpR 3 O 2015
`Page 1 of 4
`
`Doc Number: QA-032-01.02
`
`O?,tr-tS-
`
`Product: Cysteine 50mL
`
`2072115
`
`~ Lot#:
`
`Form Title: Lot Release Approval for Customer 714503
`
`. ,
`
`. ' .
`
`Eton Ex. 1022
`13 of 131
`
`

`

`~~ ofs·l'f·l'S
`
`QA Reviewed and Approved By/Date:
`
`ot✓t& -,s
`tJt ✓, :;)_-IS
`jtw08.fJ--t5
`
`~ Fail
`
`Fail
`
`Fail
`
`@>'
`
`Ensure the non-viable particulate data from the date of
`
`production of the lot has been reviewed
`
`Data in Lighthouse
`
`Comments: ~
`
`Ensure the personnel monitoring data from the date of
`
`production of the lot has been reviewed
`
`Data in BioTrends
`
`Ensure the class I 00 cleanroom EM data has been reviewed
`
`for the date of production of the lot
`
`Data in BioTrends
`
`~ Fail
`~ Fail
`~ Fail
`
`Fail
`as
`~ Fail
`
`NI A I QC-002-02 "Extract, Diluent, Sterile Drug Product
`NIA QC-076-01 "Gelman Aero 50, 0.2µ Filter Integrity Testing"
`NIA QC-073-01 "Particle Matter in lnjectables"
`
`QC-118-01 "Sterility Test Fonn"
`QC-011-02 "Endotoxin Test Record for Product Release"
`Bioburden Sample Fonn"
`
`.
`
`NIA
`NIA
`
`No
`No
`
`No
`
`No
`No
`
`]
`
`p,,tP3't~-,$"
`
`y No·~ NIA j I QC-066-01 "Method: Fill Volume"
`
`Page2 of4
`
`Doc Nwnber: QA-032-01.02
`
`Productcysteine 50mL
`
`2072115
`
`Lot#:
`
`Form Title: Lot Release Annroval for Customer 714503
`
`LJL
`
`LABORAlORIES. INC.
`
`ALLERGY
`
`Eton Ex. 1022
`14 of 131
`
`

`

`I If yes, OOS# (s)
`I If yes, EN# (s)
`I If yes, CAPA# (s)
`
`G
`(;)
`@
`
`Yes
`
`Yes
`
`Yes
`
`I
`
`I
`
`I
`
`oos
`
`ENs
`
`CAPAs
`
`Deviation Reports
`
`Page 3 of 4
`
`Doc Nwnber: QA-032-01.02
`
`Productcysteine 50mL
`
`2072115
`
`'
`
`Lot#:
`
`Form Title: Lot Release Aooroval for Customer 714503
`
`&
`..
`
`~08✓1J----/5
`
`o~-,J. -, 5
`0~✓1;,.,, s
`
`~--(;l--15'
`
`(If Investigation not complete and In ~ record please provide
`
`comment)
`
`l'N/7i:)
`
`Yes No
`
`Q f(,l~·•-5
`
`€u,._~
`
`QA Reviewed and Approved By/Date:
`
`~~
`
`Investigations complete and copy in batch record?
`
`Eton Ex. 1022
`15 of 131
`
`

`

`liJ'Yes O No ON/A
`
`N/A
`
`(cid:143)
`
`IB"Yes O No
`
`Allergy Laboratories, Inc. Certificate of Analysis
`
`MFG-037-01 "Retention Sample Form for Sandoz Inc. (ID# 714503) Drug Products"
`Material Safety Data Sheet (MSDS) (one per pallet) revision# µ/ A rH tYa-r 1-1 S-
`
`ast form in batch record
`
`to inventory By/Date:
`
`g-17-IJ
`
`(If No, provide comment)
`@
`(If No, provide comment)
`
`No
`
`e;
`
`No
`
`Yes
`
`Comments: ~""-t..,
`
`~~ Oi•\~•li,'
`
`Quality Assurance Management By/Date:
`
`Is the product acceptable for release?
`
`(Circle One)
`
`Do the investigations support the release of this product?
`
`(Circle One)
`
`By/Date: #-s/12/,,,,
`By/Date: Jla· ~ o'@-p-1s
`
`Page 4 of 4
`
`Doc Number: QA-032-01.02
`
`Product:cysteine 50mL
`
`2072115
`
`LJL Form Title: Lot Release Annroval for Customer 714503
`' ·~
`
`Lot#:
`
`LABORATORIES. INC.
`
`ALLERGY
`
`Eton Ex. 1022
`16 of 131
`
`

`

`i=g~
`es ..
`iD ",!
`'tr-~ m~S
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`~Iv,
`~~~ !~
`
`s:
`
`Doc Number: OA-006-03.01
`-... . . -
`
`. .
`
`_._, -
`
`.. -
`
`Form Effective Date (stamp):
`
`MAY O 6 2015
`
`*This form shall be copied onto
`
`MAY 05 2015
`Form Issue Date (stamp):
`autoclavable paper.
`
`Page 1 of 1
`
`activities are routine interventions, setup time will be documented on QA-006-02.
`the intervention must be documented on the corrective intervention log. Although setup
`form QA-006-02. Routine interventions do not exceed one minute. If one minute is exceeded,
`Weight checks are documented on form FAE-033-01. Corrective interventions are recorded on
`
`Cysteine 50mL
`
`2072115
`
`..._ //VV
`
`Lot#:
`Form Title: Routine Intervention Log -Line 2 Aseptic Products
`
`Product Name:
`
`~
`
`~ O<J",1~·15
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`it¾
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`t ftl !· m~
`
`... \/1
`
`·-0
`
`Eton Ex. 1022
`17 of 131
`
`

`

`1roduction management of any corrective interventions that may result in a deviation.
`Weight checks are documented on form FAE-017-01 or FAE-033-01. Routine interventions are recorded on form QA-006-01 or QA-006-03. Notify
`Although setup is a routine activity, setup times are recorded on this form to show the full length of the intervention period during setup activities.
`
`Form Effective Date (stamp):
`
`MAY O 6 2015
`
`MAY 06 2015
`Form Issue Date (stamp):
`
`(t.'43Ah-
`
`Setup End Time:
`
`*This form shall be copied onto
`
`·
`
`autoclavable paper.
`
`Cysteine 50mL
`
`Lot #:
`Form Title: Corrective Intervention Log -Line 1 & 2 Aseptic Products
`
`I Product Name:
`
`·
`
`(y: IZ~f\.
`
`~ Setup Start Time:
`
`2072115
`
`Eton Ex. 1022
`18 of 131
`
`

`

`I NIA I 7:>'(. \ ~I O)~)-o-~ 1-:::s I~
`I
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`~91 '-<r--v\
`
`I Q.S.to I
`
`762.0kg
`
`-
`
`pH
`
`.... oiajust I
`
`--
`pH
`I Toadjust
`I SOmg I 37.5kg
`
`I Q.S.
`
`I EX-10040 I Hydrochloric Acid NF
`
`3.
`
`Monohydrate
`I AP-10000 I Cysteine HCI
`
`2.
`
`I EX-10000 I Water for Injection USP I Q.S.
`
`5.
`
`I NIA
`
`NIA
`
`I EX-10000 I Water for Injection USP I 0.90mL I 686.0kg I
`
`I.
`
`Initial: ~
`t??--:)(:)-/")
`
`Production Completed:
`
`Z ··zq '!'J
`
`Yield(%):
`~ /o,-;,.o->'\
`
`/O()
`
`Started:
`
`0
`
`07--1'5--6'
`
`Qty lost:
`
`Qty manufactured: 7S0Ln62.0kg
`
`Batch Size: 7S0U762.0kg
`
`,~-•r-13
`
`/ /,-z.-r-< -s
`
`~~ -/21-,;>.-l3
`
`-G~ iBEC 1 9-201
`
`Form Effecie Dat~:
`
`Page 1 of 6
`
`Doc Number: BMR-010.00
`
`~
`
`.
`
`2072115
`
`Lot#
`
`Sandoz Inc.
`
`Cysteine HCI Injection 50mg/mL
`
`FlO00
`
`Company
`
`Formulation #
`Form Title: Cysteine Batch Manufacturing Record (750L) -Line 2
`
`Product
`
`·~
`
`Eton Ex. 1022
`19 of 131
`
`

`

`I NIA
`
`NIA
`
`I
`
`To adjust
`
`pH
`
`-
`
`I Toadjust
`
`762;0kg
`I Q.S.to
`
`-
`
`pH
`
`I EX-10000 I Water for ln~on USP I Q.S.
`
`S.
`
`I Q.S.
`
`I EX-10030 I Sodium Hydroxide NF
`
`4.
`
`Q.S.
`
`3. I EX-I 0040 I Hyc:lrQchloric Acid NF
`
`37.5kg
`
`50mg
`
`Monohydrate
`I AP-10000 I Cysteine HCI
`
`·
`
`2.
`
`N/A
`
`NIA
`
`I EX-10000 I Water forlnjection USP I 0.90ml I 686.0kg
`
`I.
`
`. ~ la011l"•I,
`
`/1,,.z.c· < ""'5
`
`~~ -//jl -:;J:>. -t3
`
`Form Effective D~e:
`
`Page 1 of6
`
`Doc Number: BMR-010.00
`
`Lot#
`
`Sandoz Inc.
`
`Cysteine HCI Injection SOmg/mL
`
`FlOOO
`
`Company
`
`Formulation #
`Form Title: Cysteine Batch Manufacturing Record (750L) -Line 2
`
`Product
`
`, ... = ... _____ .......
`
`'.~] \~:t.181
`
`Qty lost:
`
`Date Issued:
`
`Qty manufactured: 7501.J762.0kg
`
`Batch Size: 750L/762.0kg
`
`1 :~ .. i~~;,~~,~,;.1;~~JJ. ·
`::A~~~,~i~~~1iii!J~;?i~:::;.s1;:"
`:"~~~tff:i•
`W~~~~t?~::t ::,;i,"'~'~•~·::;,:~;,i:,{E", ,,:,:,,-,
`
`Initial:
`
`Yield(%):
`
`Production Completed:
`
`Production Started:
`
`1·,.DlllrJ011.1J.1114IOl:U(cid:141)-
`
`~· ~•7UJll•~IIICtllll.ou-GC.~
`
`McFadden Rachae
`
`' - '
`·er .. --
`
`Eton Ex. 1022
`20 of 131
`
`

`

`o)-;>ert5"
`
`O'?-?,-o-15
`
`I ~ I
`I ~ I
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`N/A
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`
`N/A
`
`Page 2 of6
`
`Doc Number: BMR-010.00
`
`2072115
`Lot#
`
`I
`
`o~to7
`
`0263
`
`O).'--t -S-
`
`0205
`
`c, ;)..CJl_CJ,
`
`C,\~~
`
`I
`
`I
`
`Temperature Measuring Device
`
`Weigh Scale (Range: 0.000-15.000kg)
`
`(ID# 0245 or 0244)
`Floor scale (Range: 0.00-1,500.0kg)
`
`pH Meter
`
`Mixing shaft with blade
`
`Mixer
`
`I O's~\
`
`Stainless Steel Tanlc (ID# 0331 or 0333)
`
`Sandoz Inc.
`
`Cysteine HCI Injection 50mg/mL
`
`FlO00
`
`Company
`
`Formulation #
`Form Title: Cysteine Batch Manufacturing Record (750L)-Line 2
`
`Product
`
`Eton Ex. 1022
`21 of 131
`
`

`

`5G -
`5G
`
`t.)i • 'Zo· I')
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`CJ,--ro•1<
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`?-
`
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`?-
`
`Check the raw materials for the correct name, item code and quantity. Record results on Page I of this form.
`
`250 ± 10 rpms.
`mixing blade should be set at the middle depth of the solution in the tank. Turn on the mixer and set the mixer speed at
`Insert the mixer into the WFI. Set-up the mixer so the shaft is in the center of the tank opening. The location of the
`
`is within calibration.
`
`O ")..v l
`
`Verify that the temperature measuring device ID#
`
`rpm.
`
`J.C., 0
`
`Record mixing speed:
`
`7.
`
`6.
`
`°C
`
`.;t°t · D
`
`Temperature ofWFI:
`
`5.
`
`Allow WFI to cool between the temperatures of20°C-32°C.
`When using WFI source 2 l 30HE refer to the instruction in F AE-004 for operation of the heat exchanger.
`
`WFI source (✓one): 0 2130 ~2130HE O 2131
`Add 686.0 kg of USP WFI (item #I) to the tank. Record results on Page I of the batch record.
`
`..r
`
`kg: Label the tank as QUARANTINE. Proceed to tare the scale.
`
`3 ~ I , 's
`
`Record the tank weight
`
`the tank onto the scale. Record the tank and floor scale ID#s on page 2.
`Verify that the floor scale is within calibration and record verification on page l of this form. Zero floor scale and roll
`Checklist."
`signed. Verify that cleaning has been performed by referencing MFG-031-03 "Building 2 Vial Production Cleaning
`Ensure that the mixing/compounding room # 2130 anii equipment in the room is clean and all cleaning forms have been
`number and expiration date on page I of this form.
`Ensure all raw materials are available for compounding and are within expiration date. Record the raw materials lot
`
`·
`
`4.
`
`3.
`
`2.
`
`I.
`
`Page 3 of 6
`
`DocNumber: BMR-010.00
`
`2072115
`
`Lot#
`
`Sandoz Inc.
`
`Cysteine HCI Injection 50mg/mL
`
`FlO00
`
`Company
`
`Formulation #
`Form Title: Cysteine Batch Manufacturing Record (750L) -Line 2
`
`Product
`
`Eton Ex. 1022
`22 of 131
`
`

`

`'1"'-U,· 1-(""
`
`~
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`
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`--;2---
`
`Remove a I 0mL sample and submit to QA/QC for pH testing.
`
`Using a clean container remove approximately 3L from the bottom valve of the tank and place into the top of the tank.
`
`If raw material is not dissolved within 5-10 minutes notify supervisor.
`If raw material is dissolved, proceed to Step 10.
`
`,...~A•
`
`{g
`
`Total mixing time:
`
`'3 ·• \..\ ~p-
`
`End time:
`
`Start time:
`With mixing, add 37.500kg ofCysteine HCI Monohydrate (item 02) and mix for 5-10 minutes.
`
`~:. \..\ ?.e-
`
`G''\47-5"
`Lot#: C.i1'-t,-.\..\
`37.500kg* ofCysteine is required:
`container weights below. (* indicates Critical Process Parameter)
`sampling container. If more than one sampling container is required, then repeat this step. Record the sampling
`is displaying in "kg". Tare the scale and remove the sampling container. Add the required amount of Cysteine to the
`To weigh the required amount of Cysteine. Place an empty sampling container on scale ID# 0263. Verify that the scale
`
`05-11-Ho
`
`Exp. date: oo;-11-l l,
`
`(Record lot number and expiration date on Page 1 ofthis fonn)
`
`-~
`_l_\. 16d-
`-----'-------kg (,°' \.17-rt;'
`1).90Co
`'~ \,\ ~(p
`
`(Record on page I of this fonn)
`
`Sampling container 5:
`
`lo 01'•( '
`
`Sampling container 4: ----~-"--__ kg
`
`Sampling container 3:
`
`I Sampling container 2:
`
`______ kg (,',1..(7-S-
`-~-----kg V=t"i, ... ~
`
`Sampling container I: D-OS(o
`
`11.
`
`10.
`
`9.
`
`8.
`
`Page 4 of6
`
`Doc Number: BMR-010.00
`
`2072115
`
`Lot#
`
`Sandoz Inc.
`
`Cysteine HCI Injection 50mg/mL
`
`FlOOO
`
`Company
`
`Formulation #
`Form Title: Cysteine Batch Manufacturing Record (750L)-Line 2
`
`Product
`
`Eton Ex. 1022
`23 of 131
`
`

`

`<->'i. ~o· •<
`'5[J
`
`QA/QC:
`
`07-:>o-1 ;-
`
`/l'IA-
`
`QA/QC:
`
`Page 5 of 6
`
`DocNumber: BMR-010.00
`
`2072115
`
`Lot#
`
`Include the test results and calculation in batch production records.
`
`13.
`
`Time start
`
`pH After
`
`pH Before
`
`2
`
`1
`
`Add slowly and mix 15 min before retest.
`WFI (item 01).
`correction. The required quantity of Hydrochloric Acid (item 03) or Sodium Hydroxide (item 04) must be dissolved in
`IfpH is not within range, remove a 100ml sample for QC testing to determine acid/base quantity required for pH
`
`IfpH is within range, go to step 14. If pH is not within range, go to step 13.
`
`specification of 1.20-1.30.
`
`I . d-€
`
`Record pH
`
`12.
`
`Measure pH with pH meter ID# 0205. Verify that the pH meter is in calibration.
`
`Sandoz Inc.
`
`Cysteine HCI Injection S0mg/mL
`
`FlO00
`
`Company
`
`Formulation #
`Form Title: Cysteine Batch Manufacturing Record (750L) -Line 2
`
`Product
`
`Eton Ex. 1022
`24 of 131
`
`

`

`c.,, • "Z-c;>· ' "i,.-
`
`5'u
`
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`
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`
`QA/QC:
`
`t)'/-;>o • f S-
`-:2--
`
`01,:,-0-,~
`l"'-'t
`
`QA/QC:
`
`oi-:;>o-1..,
`?--
`
`o")--,.u-1'5
`:;2.-
`
`date.
`Prior to filling operation, identify the tank as being released and include product name, lot number, volume, initials and
`QA/QC RELEASE:
`
`L.\"_ ,_
`
`Time cleaned:
`
`Equipment Cleaning Procedure -Line 2".
`Remove the mixer from the tank. Clean the mixing shaft with blade according to MFG-045 "Post-Manufacturing
`• indicates Critical Process Parameter
`supervisor)
`pH specification (1.20-) .30) pH actual results
`Measure pH with pH meter ID# 0205. Verify that the pH meter is in calibration.
`
`• (if pH does not meet ,specification, notify
`
`I .. d-~
`
`Remove a I 0mL sample into a cleaned container and submit to QA/QC for pH testing.
`
`15.
`
`I OM>"'-,
`
`Total mixing time:
`
`'-I·-' S' f>""'
`
`End time:
`
`'-f·. oS' e-
`
`Start time:
`
`Mix for 15 ± 5 minutes.
`
`19.
`
`18.
`
`17.
`
`16.
`
`-J).,J ~
`
`(' .c::::: ~ e::,,.-z.o.\<
`
`(Filling must commence within 24 hours*)
`
`Production Supervisor/date:
`
`~ " .. )-"\ P"""'
`
`• indicates Critical Process Parameter}
`Process completion time:
`
`Close the lid on the tank.
`
`Page 6 of6
`
`Doc Number: BMR-010.00
`
`2072115
`
`Lot#
`
`Q.S. WFI (item 05) to a final weight of 762kg*. (* indicates Critical Process Parameter)
`
`kg
`
`(p :l, 0
`
`/
`
`Total weight =
`
`14.
`
`Sandoz Inc.
`
`Cysteine HCI Injection 50mg/mL
`
`FIO00
`
`Company
`
`Formulation #
`Form Title: Cysteine Batch Manufacturing Record (750L) -Line 2
`
`Product
`
`. .
`
`Eton Ex. 1022
`25 of 131
`
`

`

`See PAL-002-12 for shipping box label operations.
`
`N/A
`
`See P AL-002-08 for package insert operations.
`
`See P AL-002-07 for vial carton operations.
`
`See P AL-002-01 for vial labeling operations.
`
`~
`G
`0 ~
`
`N/A
`
`N/A
`
`I 5"C,(.,){__)
`
`'3c, l(0
`
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`e-o-J
`t\1--z..HS
`ADH
`,,,---~-1
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`J5oou
`I 3'Q l(O
`7tt,-;;..,b~
`
`1 per box I
`per box
`strays I
`I 1 per tray I
`
`per tray
`s vials I
`I
`
`1
`
`I
`
`I N/A
`
`1
`
`1
`
`1
`
`S1.5mL
`
`N/A
`
`N/A
`
`L-c.,-ze,-co-O-l9.t~
`
`l-<,-z_!:)-Cl-o,<a1<
`l-e,-z3.-ut-1 ~1 eu 3
`L -<.,l ~ -CJ\-w-zw1~-
`
`AL30S0
`Shipping Box
`
`Package Insert
`
`Vial Tray
`
`Vial Label
`
`I.ST-b7 -oY fl lL/
`Stopper
`I 20mm Rubber
`I SOmL 20mm Clear G-( b .. Of Z..f ts
`Glass Vial
`I -~~--w &&~•
`
`d.(..")1 d--\\~·
`
`~"--'mL
`
`Sterilizing Filter
`Opticap 4" 0.22µ
`I Flip-off White Seal ~-Cft.~-04>"2-ZI I
`20mm Aluminum
`
`C.L\ \'Y\A 1u-4,q
`
`Shipping Box Label
`
`( current version)
`
`L-032-XX
`
`PC-40070
`
`(current version)
`
`I L-028-XX
`
`· ·
`S
`
`(current version)
`
`L-023-XX
`
`I
`
`(current version)
`
`I L-018-XX
`
`I KVGLS041il13
`
`S-023
`
`ST-07
`
`G-16
`
`CYS-002
`
`I
`
`I
`
`I
`
`I
`
`7.
`
`6.
`
`s.
`
`4.
`
`3.
`
`2.
`
`1.
`
`I
`
`I
`
`10.
`
`9.
`
`JAN 3 0 2014
`
`Form Issue Date:
`
`FEB IO 2014
`
`Form Effective Date:
`
`Page 1 of9
`
`~e. ~~ ~ l ..fuy-e,u<s\t)ma-a.pp(W~ ~ MC 01-z.q-14
`
`ol • &fi'•I
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`
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`
`Custome\ Approval/date:
`
`\
`
`QA Appr,val/date:
`
`Department Approval/date:
`
`Originator/date:
`
`Doc Number: VMR-014.00
`
`S0mL Cysteine HCI Injection Vial Manufacturing Record -Line 2
`
`01ri-'ll"J
`
`Eton Ex. 1022
`26 of 131
`
`

`

`See P AL-002-12 for shipping box label operations.
`
`NIA
`
`See PAL-002:.08 fut paclaige uw,rt operations ..
`See PAL-002-07 for vial carlol'.l operatioll$.
`
`See PAL-002-01 for vial labeling operations.
`
`NIA
`
`NIA
`
`~, ... v,.,~,.,,
`
`rs
`
`Rou
`
`1 perbox
`
`perbc>x
`strays
`
`I l.r,ettray
`
`per.tray
`5 vials
`
`I NIA
`
`NIA
`
`NIA
`
`I (cummt version) Shippiilg Box Label
`
`L-032-XX
`
`10.
`
`AL3050
`ShippmgBox
`(~tv~iQD) Pacqge Insert
`
`PC40070
`
`Vial Tray
`
`I k028-XX
`I (currimt version)
`
`L-()23-XX.
`
`I
`
`9.
`
`I (currentversion) . Vial Label
`
`L-018-XX
`
`I
`
`Sterilizing Filter
`I KVGLS04HH3 Optii:ap 4" 0.22)&
`
`I Flip-off White Seal
`20mm Aluminum
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