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`EXHIBIT 1
`
`
`Declaration of John Geissler
`December 6, 2019
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`IN THE UNITED STATES DISTRICT COURT
`FOR THE WESTERN DISTRICT OF NORTH CAROLINA
`ASHEVILLE DIVISION
`
`EXELA PHARMA SCIENCES, LLC,
`
`Civil Action No. 1:19-CV-318
`
`vs.
`
`SANDOZ, INC.,
`
`Plaintiff,
`
`Defendant.
`
`DECLARATION OF
`JOHN GEISSLER
`
`I, JOHN GEISSLER, being duly sworn, depose and state as follows:
`
`1.
`
`My name is John Geissler. I am over 21 years of age and competent to testify to
`
`the statement set forth in this declaration.
`
`2.
`
`The facts set forth in this declaration are based on my personal knowledge and
`
`upon information available to me through the files and records of Sandoz Inc. (Sandoz). If
`
`called upon as a witness, I could and would testify to those facts.
`
`3.
`
`Since November 2018, I have served as the Global Head, GxP Audit and CAR-T
`
`Compliance at Novartis. Before that, I was the Global Head, Compliance, Incident Management
`
`and Audit at Novartis since July 2016. My responsibilities during this time period have included
`
`current Good Manufacturing Practice (GMP) compliance, pharmacovigilance, and overseeing
`
`the supplier audit programs across all Novartis Technical Operations. From February 2014 to
`
`July 2016, I served as the Global Head, Compliance and Audit at Sandoz, a division of Novartis.
`
`I started my employment with Novartis in August 2012 as the Executive Director and Head,
`
`GMP Compliance, until February 2014. I have held positions relating to manufacturing and
`
`product quality and good compliance practices (GxP) at Sandoz and other pharmaceutical
`
`companies since 1999. I earned a B.S. in Chemistry from Rutgers University in 1989.
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`4.
`
`Until 2016, Allergy Laboratories, Inc. (Allergy Labs) was the contract
`
`manufacturer that Sandoz used to produce L-Cysteine Hydrochloride Injection, USP, 50 mg/mL
`
`(L-Cysteine). Based on documents in our files that I have reviewed, Allergy Labs manufactured
`
`this L-Cysteine product at least as far back as 2008. At that time, Allergy Labs contract
`
`manufactured this product for Parenta Pharmaceuticals (an EBEWE company). Attached as
`
`Exhibit A is a true and correct copy of Parenta Pharmaceuticals 2008 Annual Product Review
`
`(APR) for L-Cysteine Hydrochloride Injection, USP (50 mg/mL). This document, dated June
`
`19, 2009, states that EBEWE Parenta Pharmaceuticals was the owner of the product, and Allergy
`
`Labs was its manufacturer. The attachment to this document states that the aluminum content
`
`was within the specification, under 5000 ppb, and that all batch records reviewed for the relevant
`
`time period contained passing aluminum content results, based on this specification. In 2009,
`
`Sandoz acquired EBEWE. See https://www.pharmaceuticalonline.com/doc/sandoz-completes-
`
`acquisition-of-ebewe-pharma-0001. It is my understanding that Sandoz acquired the L-Cysteine
`
`product as part of this acquisition and continued to engage Allergy Labs as the contract
`
`manufacturer for this product until 2016.
`
`5.
`
`In late 2014, following an FDA manufacturing inspection, Allergy Labs
`
`suspended production of L-Cysteine at its Oklahoma City, OK facility based on inspectional
`
`observations. At this time, Sandoz placed its L-Cysteine inventory on distribution hold pending
`
`a risk assessment. In or around January 2015, FDA approached Sandoz to explore options for
`
`increasing the supply of L-Cysteine. To address the shortage of L-Cysteine in the U.S market,
`
`Sandoz developed and implemented an “as-is” technology transfer (tech transfer) of the
`
`manufacturing process from Allergy Labs to the Sandoz site in Boucherville, Canada (BV). I
`
`played a major role in developing the strategy for the “as-is” tech transfer.
`
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`6.
`
`The BV site in Canada is, and has been since at least 2015, an FDA-registered
`
`manufacturing facility under Section 510 of the Federal Food, Drug and Cosmetic Act (21 USC
`
`360) and 21 CFR Part 207. The BV site is currently registered under “Services Pharmaceutiques
`
`Avara Boucherville Inc.,” which is currently owned by Sandoz. The registration can be verified
`
`at FDA’s Drug Establishments Current Registration Site, available at:
`
`https://www.accessdata.fda.gov/scripts/cder/drls/getdrls.cfm. Attached as Exhibit B is a true
`
`and correct copy of the data from FDA’s website demonstrating that Services Pharmaceutiques
`
`Avara Boucherville Inc. is an FDA-registered manufacturing facility. The BV site has been
`
`involved in sterile drug manufacturing since at least 1997. The facility and sterile filling line
`
`manufacturing equipment used to manufacture the L-Cysteine product have been in operations
`
`since 2008.
`
`7.
`
`In June 2015, a cross-functional team, including manufacturing quality experts,
`
`finalized a written protocol to evaluate the process and specifications for transfer to the BV site.
`
`The “as-is” transfer to the BV site maintained the formulation, product specifications, and
`
`manufacturing technologies used to manufacture the product at Allergy Labs. The transfer also
`
`provided for the same Active Pharmaceutical Ingredient (API) supplier, an equivalent process for
`
`formulation and filling 10 mL vials, and equivalent primary packaging and labeling. The tech
`
`transfer protocol also evaluated the product’s critical quality attributes and found that the BV
`
`site’s response and control strategies were adequate. The product specifications for release of L-
`
`Cysteine finished product, including the test method and limits for aluminum content (not more
`
`than 5000 ppb) were not changed during the tech transfer to the BV site.
`
`8.
`
`In addition, the labeling of both products manufactured by Allergy Labs and the
`
`BV site refer to the same maximum aluminum content level. The statement on the immediate
`
`3
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`container labels that the product “Contains no more than 5,000 mcg/L of aluminum” was not
`
`changed. No changes were made to the labeling, other than manufacturer-related changes, such
`
`as manufacturer name and NDC numbers. The labeling complies with FDA regulation, 21 CFR
`
`201.323, which requires the maximum level of aluminum present at expiry to be stated on the
`
`immediate container label of all small volume parenteral (SVP) drug products used in total
`
`parenteral nutrition. An SVP is defined as a parenteral product that contains less than 100 mL.
`
`See, e.g., https://www.fda.gov/media/108408/download. Because L-Cysteine is supplied in 10
`
`mL vials, it is considered an SVP. The labeling also maintains without change the aluminum
`
`warning statement required by 21 CFR 201.323(e).
`
`9.
`
`On January 21, 2016, Sandoz submitted a letter to FDA requesting the agency’s
`
`agreement in writing to allow importation of L-Cysteine from the BV site in Canada. The letter
`
`to FDA included information and records requested by FDA’s Office of Drug Shortage,
`
`including the tests and specifications for L-Cysteine product. A true and correct copy of a
`
`document titled “Inspection Plan” provided as an attachment to the letter to FDA is attached as
`
`Exhibit C. The Inspection Plan references the test methods and established specifications for
`
`the product during batch release testing, including aluminum content levels, which remained
`
`unchanged after the tech transfer from Allergy Labs to the BV site.
`
`10.
`
`The BV site has maintained adequately controlled manufacturing operations and a
`
`high level of compliance with FDA’s Current Good Manufacturing Practice (cGMP)
`
`requirements. In August 2016 and June 2018, FDA investigators performed cGMP inspections
`
`of the BV site. FDA investigators evaluated the facilities and equipment, packaging and
`
`labeling, production system, and quality system at the BV site. FDA did not issue a Form 483
`
`for any inspectional observations following either site inspection. FDA classified both
`
`4
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`inspections as “no action indicated” (NAI), which means the agency determined that the BV site
`
`is in an acceptable state of cGMP compliance, and FDA closed out both inspections.
`
`11.
`
`Before each batch is released for distribution it is tested to ensure that it meets
`
`specifications. Since the transfer to the BV facility, there have not been any out of specification
`
`(OOS) testing results related to aluminum content levels. In addition, under 21 CFR 310.305,
`
`Sandoz is required to maintain records and report to FDA any serious, unexpected adverse drug
`
`experiences associated with any drug that is not the subject of approved drug application. To my
`
`knowledge, Sandoz has never received any adverse events reports related to L-Cysteine.
`
`12.
`
`From April 2016 to September 2019, a total of 109 lots of L-Cysteine product
`
`were imported from the BV site for U.S. distribution. All of these batches were within pre-
`
`established specifications, including aluminum levels that were substantially below the limit for
`
`aluminum content. Lot numbers JW2797 and JW3294 were the last batches of L-Cysteine
`
`imported from the BV site. As set forth in the Certificates of Analyses (CoAs) for these batches,
`
`the release testing results show that aluminum content levels were “< 375 ppb.” True and correct
`
`copies of the CoAs for L-Cysteine lot numbers JW2797 and JW3294 are attached hereto as
`
`Exhibit D. In addition, testing of aluminum content levels is performed at established intervals
`
`during the product’s two-year shelf-life, referred to as a stability monitoring program. Stability
`
`data collected for L-Cysteine since the tech transfer have consistently demonstrated that
`
`aluminum levels remained well below the limit throughout the product’s expiry.
`
`13.
`
`For each L-Cysteine lot offered for importation into the U.S., Sandoz included
`
`CoAs as evidence of manufacturing and product quality. FDA has never raised any concerns
`
`about the aluminum levels in Sandoz’s L-Cysteine product. Nor has FDA ever asked Sandoz
`
`5
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`any questions or expressed any concern about the disclosure on the immediate container label
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`regarding the aluminum content, which has been in place without change for many years.
`
`14.
`
` Sandoz did not increase the amount of L-Cysteine it imported after FDA
`
`approved ELCYS in April 2019. Exhibit E, attached to this Declaration, lists the batches,
`
`quantities, and entry dates for L-Cysteine Sandoz imported between January 2019 and August
`
`2019 before FDA requested Sandoz stop importing the product.
`
`15.
`
`Sandoz has not imported any L-Cysteine since FDA requested that Sandoz stop
`
`importing on September 3, 2019. Sandoz has not distributed any L-Cysteine since FDA
`
`requested that Sandoz stop distribution on October 8, 2019. In fact, Sandoz has not sold any L-
`
`Cysteine product that was manufactured after the date on which ELCYS was approved by FDA.
`
`I am informed that on December 2, 2019, Sandoz had 25,690 units in its own inventory in the
`
`U.S. Additionally, Sandoz has 25,417.3 units in inventory in Canada that it was prohibited from
`
`importing into the U.S.
`
`6
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`16.
`
`On November 7, 2019, I participated in a telephone conference with Valerie
`
`Jensen R.Ph. (Associate Director, FDA's Drug Shortage Staff) and Jouhayna Saliba, Pharm.D.
`
`(Team Leader, FDA's Drug Shortage Staff). I informed them that a Complaint had been filed by
`
`Exela Pharmaceuticals seeking monetary damages and injunctive relief against Sandoz related to
`
`marketing L-Cysteine. When she learned that Exela had complained about aluminum levels in
`
`the Sandoz product, Ms. Jensen stated that the Agency "has evaluated the Sandoz product and
`
`has no concerns from that perspective." A true and correct copy of an email summary of the call
`
`dated November 7, 2019 to Sandoz personnel is incorporated herein by reference and attached
`
`hereto as Exhibit F.
`
`I declare under pen?lty of perjury that the foregoing is true and correct. Executed this
`
`!' '~
`2_ day of December 2019.
`
`'
`
`( -?~. / 4 _
`By: ~ ~-z------
`John Geissler
`Global Head
`Compliance, Incident Management, and
`Audit
`
`7
`
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`
`
`
`EXHIBIT A
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`PARENTI'.®
`
`pharmaceuticals
`an Ebewe Pharma Company
`
`2008
`
`Annual Product Review
`L-Cysteine Hydrochloride Injection, USP
`(50 mg/mL)
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`PARENT1'.."
`
`pharmaceuticals
`an £bewe Pharma Company
`
`2008 Annual Product Review
`L-Cysteine Hydrochloride Injection, USP (50 mg/mL}
`2008 Annual Product Review
`L-Cysteine Hydrochloride Injection, USP (50 mg/mL)
`
`Section
`I.
`n.
`III.
`IV.
`v.
`VI.
`VII.
`VIII.
`
`IX.
`
`Title
`Retains
`..................................... .
`Deviations/Investigations/Rework
`..................................................... .
`Customer Complaints
`........................................................... .
`Returned Goods
`Recalls
`.................................................................... .
`Process/Equipment Change Control ..................................... .
`oos
`......................................................................... .
`Recommendations/CAP A, Previous Recommendations, and
`Conclusions
`.................................................................... .
`..................................................... .
`Review and Approval
`
`Page
`3
`3
`4
`4
`5
`5
`5
`
`6
`
`7
`
`Attachments
`
`Attachment I
`
`Attachment II
`Attachment III
`Attachment IV
`Attachment V
`
`2008 Annual Product Review from Allergy
`Laboratories, Inc.
`2008 Summary of Customer Complaints
`2008 Returned Goods Summary
`2008 Annual Report, Distribution Data
`2008 Recall Statement
`
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`PARENT A®
`
`pharmaceuticals
`an Ebewe Pharma Company
`
`2008 Annual Product Review
`L-Cysteine Hydrochloride Injection, USP (50 mg/mL)
`
`The 2008 Annual Product Review was compiled in accordance with 21 CFR
`314.81(b)(2) and 21 CFR 211.180(e) as well as Ebewe ParentaPharmaceutical's
`internal procedure SOP-REG-01 0(02), "Annual Product Review." The Annual
`Product Review encompasses the 2008 calendar year from January 1, 2008 to
`December 31, 2008. This APR contains information on Ebewe Parenta
`Pharmaceuticals' product L-Cysteine HCl Injection, USP manufactured,
`commercially marketed and/or returned in 2008. This APR was compiled with input
`from Ebewe Parenta Pharmaceuticals (Parenta), the owner of the product and Allergy
`Laboratories, Inc (Allergy), the manufacturer of the product.
`
`I.
`
`II.
`
`Retains
`a. Allergy provided a summary in Attachment I. Section XI, Retention
`Sample Review, states that a visual inspection of the lots ofL-Cysteine
`HCl Injection showed there were no issues or anomalies with the retention
`samples.
`
`b. There are no recommendations.
`
`Deviations/Investigations/Rework
`a. There were two Problem Analysis and Corrective Action Reports
`(P A CARs) directly related to the production of L-Cysteine HCl Injection,
`USP reported by Allergy. See Attachment I, section VII, PACARs. Table
`1 summarizes the deviations and impact. There was no impact on the
`product and these issues are also discussed in section VII, OOS, of this
`report.
`
`b. There were no deviations reported by Ebewe Parenta Pharmaceuticals
`during the review period.
`
`c. There are no recommendations.
`
`Table 1: 2008 Deviations for L-Cysteine HCI Injection, USP
`
`PACAR
`Number
`PAC-079-103108
`
`PAC- 080-103108
`
`Description
`
`Impact
`
`High OOS assay results were
`obtained for one lot of L-Cysteine
`HCl, USP API. No root cause was
`found. Material was rejected.
`High OOS assay results were
`obtained for one lot of L-Cysteine
`HCl, USP API. No root cause was
`found but suspected lab error.
`Material was retested by vendor
`
`No impact to
`distributed product.
`
`No impact to
`distributed product.
`
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`PARENT A"
`
`pharmaceuticals
`an Ebewe Pharma Company
`
`2008 Annual Product Review
`L-Cysteine Hydrochloride Injection, USP (50 mg/mL)
`
`and third party lab with success.
`Drug product manufactured with
`this material has met all
`specifications.
`
`III. Customer Complaints
`
`a. There were no complaints involving L-Cysteine HCl Injection, USP
`during the review period. This is the same as the 2007 review period
`where there were no complaints recorded. See Attachment I, section III,
`Complaints and Attachment II.
`
`b. There are no recommendations.
`
`IV.
`
`Returned Goods
`a. Table 2 below details the level of returns for each product code of L(cid:173)
`Cysteine HCl Injection, USP. There were 19,617 cases ofNDC # 66758-
`004-01 (1 case= 10 vials) and 15,250 cases (1 case= 5 vials) ofNDC#
`66578-005-01 distributed during the review period. See Attachment I,
`section II, Returned and Salvaged Goods, and also Attachment III.
`
`Table 2: 2008 Returned Goods for L-Cysteine HCI Injection, USP
`
`Product
`Name
`
`Strength
`(mglmL)
`
`NDC#
`
`Fill Quantity
`(mL)
`
`66758-004-01
`
`10
`
`1,093 vials
`
`L-Cysteine
`
`50
`
`66758-005-0 I
`
`50
`
`331 vials
`
`Return Evaluation
`
`673 vials for Expired/
`Short-Dated Product
`
`210 vials for Damage
`
`210 vials for Shortage*
`56 vials for Expired/ Short-
`Dated Product
`
`235 vials for Damage
`
`40 vials for Shortage*
`*shortage IS defined as "an mcorrect number ofvmls sent to the
`customer". Typically the customer returns the entire quantity so that the
`distribution warehouse can investigate the error.
`
`b. There are no recommendations for improvements as this is a relatively low
`number of returns compared to the amount distributed. The rates of return
`for NDCs 66758-004-01 and 66758-005-01are 0.56% and 0.43%,
`respectively.
`
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`PARENTI'..®
`
`pharmaceuticals
`an Ebewe Pharma Company
`
`2008 Annual Product Review
`L-Cysteine Hydrochloride Injection, USP (50 mg/mL)
`
`V.
`
`ReeaUs
`a. No recalls of L-Cysteine HCI Injection, USP were initiated in 2008. See
`Attachment I, section IX, Recalls, and also Attachment V.
`
`b. There are no recommendations.
`
`VI.
`
`Process/Equipment Change Control
`a. Allergy initiated three equipment change control documents called Change
`Control Protocols (CCP) during the review period. See Attachment I,
`section VIlli, Change Control. There were no change controls initiated at
`Parenta during the review period. All three change controls relating to
`Cysteine HCI Injection, USP (50 mg/mL) are summarized in Table 3
`below.
`
`Table 3: 2008 Change Controls for Cysteine HCl Injeetion, USP
`
`Change
`Control
`Number
`CCP-016
`
`CCP-017
`
`CCP-019
`
`Description
`
`Disposition
`
`This was determined to be a
`minor change with minimal
`impact on the product.
`
`Upgrade the rotary unscrambling
`table located in the Class 100
`Aseptic Filling Suite. The new unit
`replaces antiquated equipment and
`requires fewer adjustments during
`manufacturing.
`Upgrade the mild steel floor deck
`scale in the Class 10,000 mixing
`room. The new unit is a rust-free
`stainless steel floor scale deck.
`This was determined to be a
`Replace the shrink wrapper for
`sterile drug production to a newer, minor change with minimal
`impact on the product.
`more efficient model.
`
`This was determined to be a
`minor change with minimal
`impact on the product
`
`b. Refer to Annual Report for document changes.
`
`c. There are no recommendations associated with these change controls.
`
`VII. OOS
`a. There were two (2) Out-of-Specification Investigation Reports initiated in
`2008 directly related to commercial product as detailed in Table 4 below:
`
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`PARENTI'.."
`
`pharmaceuticals
`an Ebewe Pharma Company
`Table 4: 2008 OOS Reports for Cysteine HCI Injection, USP
`
`2008 Annual Product Review
`L-Cysteine Hydrochloride Injection, USP (50 mg/mL)
`
`OOSR
`Number/Product
`OOSR08-001
`
`OOSR08-009
`
`Description
`
`Conclusion
`
`Corrective Action
`
`OOS assay results for There was an
`Cysteine HCl, USP
`unidentified
`laboratory error.
`
`N/A-material was rejected.
`
`API lot number CR-
`4111
`OOS assay results for Laboratory error Redevelopment of assay titration
`-
`relating to the
`at Parenta. Increased controls
`Cysteine HCl, USP
`titration
`were added along with
`requirement to use commercially
`technique.
`prepared reagents.
`Vendor and third party lab
`provided retesting of the material.
`
`API lot number CR-
`4287
`
`VIII. Recommendations/CAP A, Previous Recommendations, and Conclusions:
`a. Recommendations/CAP A: No recommendations.
`
`b. Previous Recommendations: None
`
`c. Conclusions: All systems are functioning as intended. The manufacturing
`and testing processes are operating in a state of control.
`
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`PARENT A®
`
`pharmaceuticals
`an Ebewe Pharma Company
`
`2008 Annual Product Review
`L-Cysteine Hydrochloride Injection, USP (50 mg/mL)
`
`IX. Review and Approval:
`
`.. ~~A~~
`
`Rosenstack/V.P. of Marketing
`
`Date
`
`Date
`
`Dat~
`
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`PARENTi'..®
`
`pharmaceuticals
`an Ebewe Pharma Company
`
`2008 Annual Product Review
`L-Cysteine Hydrochloride Injection, USP (50 mglmL)
`
`ATTACHMENT I
`
`2008 Annual Product Review from
`Allergy Laboratories, Inc. for
`L-Cysteine HCl Injection, USP
`50 mg/mL, 10 mL and 50 mL fill
`
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`Sterile Injectable Drugs
`L-Cysteine HCIInjection USP 50mg/ml, 10ml & 50ml fill
`Page 1 of 7
`Review Period:
`Jan
`2008- December 31 2008
`
`L-Cysteine HCI Injection USP product description:
`
`L-Cysteine HCI Injection USP 50mg/ml is a sterile, nonpyrogenic solution, with each ml
`containing 50mg of L-Cysteine HCI Monohydrate USP and Water for Injection. The pH range is
`1.0- 2.5. L-Cysteine is a sulfur-containing amino acid. In premixed solutions of crystalline
`amino acids, Cysteine is relatively unstable over time, eventually converting to insoluble
`Cysteine. To avoid such precipitation, L-Cysteine HCI Injection USP is intended to be used an
`additive with Crystalline Amino Acid Injections immediately prior to administration to the patient.
`
`L-Cysteine HCI!njection USP is manufactured on a contract basis for Parenta Pharmaceuticals,
`Inc. of West Columbia, South Carolina. It is manufactured in two fill volumes, 1Om I and 50ml.
`The manufacturing process and testing specifications are identical for the two fill volumes.
`During the review period of 01/01/08 through 12/31/08, a total of 31ots of L-Cysteine HCI
`Injection USP 50mg/ml 10ml fill were manufactured, and a total of 11 lots of 50ml fill were
`manufactured.
`
`The total number of L-Cysteine HCIInjection USP 50mg/ml 10ml fill lots manufactured is down
`2 lots from the previous year 2007, in which 5 total lots were manufactured. The total number
`of 50ml fill lots is up one lot from 2007, in which 10 total lots were manufactured.
`
`Descriptions for the individual products are contained herein.
`
`The following areas were reviewed:
`
`Rejected/Destroyed batches
`I.
`Returned/Salvaged goods
`II.
`Complaints
`Ill.
`Adverse Events
`IV.
`Stability
`V.
`Deviations
`VI.
`PACARs
`VII.
`VIII. Change Control
`IX.
`Recalls
`Batch Records I Production Review
`X.
`XI.
`Retention Samples
`
`A summary of each area reviewed follows and, in come cases, supported with tables or graphs:
`
`I.
`
`Rejected I Destroyed Batches:
`
`There were no rejected/destroyed lots of L-Cysteine HCI Injection USP 50mg/ml, 1Om! or 50ml
`fill, for the review period. This remains the sam_::,trom the previous review period in 2007, where
`there were also no rejected/destroyed lots.
`
`L
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`2008 ANNUAL PRODUCT REVIEW
`Sterile Injectable Drugs
`L-Cysteine HCIInjection USP 50mg/ml, 10ml & 50ml fill
`Page 2 of 7
`
`Oklahoma City, OK 73109
`
`II.
`
`Returned/Salvaged Goods:
`
`There were no returned/salvaged lots of L-Cysteine HCIInjection USP 50mg/ml, 10ml or 50ml
`fill, for the review period. This remains the same from the previous review period in 2007, where
`there were also no returned/salvaged lots reported.
`
`Ill.
`
`Complaints
`
`There were no complaints involving L-Cysteine HCIInjection USP 50mg/ml, 10ml or 50ml, fill
`during the review period. This remains the same from the previous review period in 2007, where
`there were also no complaints reported.
`
`IV.
`
`Adverse Events
`
`There were no adverse events reported to Allergy Laboratories, Inc. concerning L-Cysteine HCI
`Injection USP 50mg/ml, 10ml or 50ml fill during the review period. This remains the same from
`the previous review period in 2007, where there were also no adverse events reported.
`
`V.
`
`Stability Testing
`
`Stability testing and documentation are the responsibility of Parenta Pharmaceuticals, Inc. All
`inquiries regarding stability of drug products should be made to Parenta.
`
`VI.
`
`Deviations
`
`There were no deviations reported for L-Cysteine HCIInjection USP 50mg/ml 10ml or 50ml fill
`during the review period. This remains the same from the previous review period in 2007,
`where there were also no deviations reported.
`
`VII.
`
`PACARs IOOS)
`
`There were two PACARs (OOS) associated with the manufacturing of L-Cysteine HCIInjection
`USP 50mg/ml 1Om I & 50ml fill during the review period, both involving the L-Cysteine active
`pharmaceutical ingredient (API). This remains the same from the previous review period in
`2007, in which there were also two PACARs reported. Summaries of the PACARs are as
`follows:
`
`• PAC-079-103108:
`
`• PAC-080-103108:
`
`The assay portion of USP release testing for Cysteine API
`exhibited high results on several test replicates. No root cause
`was found. A copy of the PACAR with complete explanation is
`attached.
`
`The assay portion of USP release testing for Cysteine API
`exhibited high results on several test replicates. No root cause
`was found. A copy of the PACAR with complete explanation is
`attached.
`
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`Oklahoma City, OK 73109
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`2008 A.NNUIA.L
`Sterile Injectable Drugs
`L-Cysteine HCIInjection USP 50mg/ml, 10ml & 50ml fill
`Review Period:
`Page 3 of 7
`Janua
`2008- December 31 2008
`
`There was one PACAR associated with environmental monitoring (EM) excursions (surface
`count excursion). An investigation was completed, and retraining performed where applicable.
`All products passed final release testing, including sterility, and were subsequently released with
`no further issues. A brief summary of this excursion is as follows. A copy of the PACAR
`Narrative is attached.
`
`• PAC-037-080508:
`
`Airlock/Degown Room floor. Bacterial isolates identified as
`Bacillus cereus (a common environmental organism).
`
`VIII. Change Control
`
`There were three Change Control Protocols (CCP) documented during the review period that
`could possibly have an effect on the manufacturing of L-Cysteine HCIInjection USP 50mg/ml
`1 Oml & 50ml fill. The number of change control protocols is up from the previous review period
`in 2007, in which there was one CCP documented. Summaries of the CCPs are as follows:
`
`• CCP-016:
`
`• CCP-017:
`
`The rotary unscrambling table was upgraded in the Class 100 Aseptic
`Filling Suite. It replaced antiquated equipment and requires fewer
`adjustments during manufacturing. This was determined to be a minor
`change with minimal potential to have an adverse effect on the safety or
`efficacy of the product. A copy of the completed CCP is attached.
`
`The mild steel floor scale deck was upgraded in the Class 10,000 mixing
`room to a rust-free, stainless steel floor scale deck. This was determined
`to be a minor change with minimal potential to have an adverse effect on
`the safety or efficacy of the product. A copy of the completed CCP is
`attached.
`
`• CCP-019:
`
`The shrink-wrapper for sterile drug production was replaced with a newer,
`more efficient model. This was determined to be a minor change with
`minimal potential to have an adverse effect on the safety or efficacy of the
`product. A copy of the completed CCP is attached.
`
`IX.
`
`Recalls
`
`There were no recalls of L-Cysteine HCIInjection USP 50mg/ml 10ml or 50ml fill during the
`review period. This remains the same from the previous review period in 2007, where there
`were also no recalls reported.
`
`X.
`
`Batch Record I Production Review
`
`Batch records from all lots manufactured were reviewed. Attached data for L-Cysteine HCI
`Injection USP 50mg/ml 1Om I & 50ml fill indicates lot numbers of the lots manufactured, release
`dates, and results from release tests and other required specifications. Specifications are in
`place for drug products for the following categories:
`
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`Eton Pharmaceuticals v. Exela Pharma Sciences - PGR2020-00064
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`

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`2008 ANNUAL PRODUCT REVIEW
`Sterile Injectable Drugs
`L-Cysteine HCIInjection USP 50mg/ml, 10ml & 50ml fill
`Review Period:
`2008 - December 31 2008
`
`• Filter Bubble Point (Opticap Filter): not less than 50psi. All batch records reviewed for the
`period contained passing bubble point results.
`
`• Filter Bubble Point (Aspirator Vent Filter): not less than 13psi. All batch records reviewed
`for the period contained passing bubble point results.
`
`• Rejected vials for defects: no more than 10%. Each lot of L-Cysteine HCIInjection USP
`50mg/ml 10ml & 50ml fill manufactured is 100% inspected for bad caps, stoppers, broken
`vials, and high/low fill volume. During the review, there were no lots whose rejects
`exceeded the limit. A graph of the reject percentages (attached) appeared flat and
`consistent for all lots, with no unusual spikes in either direction.
`
`• Appearance of Product: conforms. Each vial from each lot of L-Cysteine HCIInjection
`USP 50mg/ml 1Om I & 50ml fill is 100% inspected for the appearance of the product as
`compared to individual product descriptions. During the review, there were no lots that
`failed the appearance inspection.
`
`• Appearance of Container/Closure: conforms. The container/closure system from each
`vial from each lot of L-Cysteine HCIInjection USP 50mg/ml 10ml & 50ml fill is 100%
`inspected for improper seals, invaginated stoppers, leakage, or physical alteration. During