CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
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`212535Orig1s000
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`PRODUCT QUALITY REVIEW(S)
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`Memorandum
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`DEPARTMENT OF HEALTH AND HUMAN
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`SERVICES PUBLIC HEALTH SERVICE
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`FOOD AND DRUG ADMINISTRATION
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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`Date:
`From:
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`Through:
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`December 12,2019
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`Hitesh Shrofl', Ph.D.
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`Application Technical Lead, Branch V
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`Division of New Drug Products 11
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`Office of New Drug Products
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`Moo-Jhong Rhee, Ph.D.
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`Chief, Branch V
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`Division of New Drug Products 11
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`Office of New Drug Products
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`To:
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`CMC Review #1 of NDA 212535
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`Subject: Final Recommendation for NDA 212535
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`At the time when the CMC Review #1 was completed on November 22, 2019 it had noted the
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`following pending issues:
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`The label/labeling issues have not been completely resolved.
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`Because of these deficiencies, the NDA was not recommended for approval fiom the OPQ
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`perspective.
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`The applicant submitted the revised Prescribing Information (PI) and container/carton labels on
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`December 1 1, 2019. The resubmitted CMC sections ofthe labeling/labels deemedacceptable. (See
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`the Attachment 1)
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`The applicant submitted additional admixture stability studies results in the amendment dated
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`December 6, 2019. Based on the admixture stability studies it is recommended that when Nouress1s
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`admixed with electrolytes e. g.
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`etc. it should not be refrigerated. The admixture should be administered within 24 homs at room
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`temperature. The unused portion should be discarded.
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`his NDA is now recommended for Approval from the OPQ perspective.
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`W T
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`Application Technical Lead’s Assessment and Signature
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`The NDA is recommended for Approval fi'om quality perspective.
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`a
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`Digitally signed by Hitesh N.
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`Hltesh N
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`HlteSh Shroff, Ph-D-
`° DN:c=U5.o=U.5.Government,
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`Application Technical Lead’
`ou=HHS, ou=FDA. ou=Peop|e.
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`Biancii v Division ofNew Drug Products 11 S h roff _S g;g:gfg::g',;:g:-,L?gg;;;:g°°
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`December 12, 2019
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`Date: 2019.12.12 15:43:05 45'00'
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`(b) (4)
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`Attachment 1
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`Memorandum
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
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`PUBLIC I-DEALTH SERVICE
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`FOOD AND DRUG ADMINISTRATION
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`CENTER FOR DRUG EVALUATION AND RESEARCH
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`Date:
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`From:
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`Through:
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`December 11, 2019
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`Hong Cai, Ph.D.
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`Drug Product Reviewer
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`Office of New Drug Products
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`Branch IV/DNDP II
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`Moo-Jhong Rhee, Ph.D.
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`Chief, Branch IV
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`Office of New Drug Products
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`Branch IV/DNDP II
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`To:
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`Drug Product/Labeling Review #1 of NDA212535
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`for NouressTM (cysteine hydrochloride injection)
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`Subject:
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`Final Recommendation
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`The applicant submitted revised Prescribing Information, container/carton labels and a
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`stability study report for TPN admixture on December 11, 2019 (SN0042) and December
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`6, 2019 (SN0040), respectively, afler the completion of the Labeling Review #1 on
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`9/12/19 and Drug Product Review #1 on November 22, 2019.
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`The updated Prescribing Information (PI), container and carton labels have been
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`satisfactorily revised as were recommended in the Labeling Review #1.
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`In the admixture stability studies, the applicant excluded two electrolyte components,
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`(b) ‘4) from the TPN
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`admixture containing Nouress unlike the previous in vitro studies. The ratio of Nouress to
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`Amino Acids (AAs) is kept as 22 mg to 1 gram based on the recommended dosage of
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`Nouress for neonate (See Section 2.5 of P1). In this study, the applicant included an
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`additional arm using the approved drug ELCYS for side by side comparison with
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`Nouress. The study protocol is CON-FS-0598 Rev00 and the study report is FEA—AR—19-
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`0028 Rev.01. The study results are summarized as the following:
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`1. No visual particulate matters observed in the study TPN admixture containing
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`Nouress afier the storage period of 24-hour at room temperature or 24-hour room
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`temperature post 24-hour refiigeration. This suggests the Visual particles observed
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`after the refiigeration in the previous study is most likely due to the addition of
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`the two electrolytes.
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`(b) ‘4) are comparable between
`2. The assay values of cysteine and the impurity
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`Nouress and the approved drug ELCYS. Detailed data is shown in the table
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`below. It is noted that the assay values ofNouress are in the range of
`(b) ‘4) %
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`E2; immediately after mixing with AAs and Glucose (initial time point). This is
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b)
`(4)
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`hwa'thmeapecmiAflhoughtheenetemeahavenetheenmumghly
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`mmfigmadyatmmmafimmmmsimflmmmemmmbms,
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`2fl19,hewever.aimflarebservafieneeemedwflhfl1eappmwddmgm5
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`(”W”).Thiesuwtattelewassaywlueatteinifialfimepuinmmy
`ll
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`netheNemeaa specific. FmtherJhereisadeereueefessayvaluee ever
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`anal-age. Thedeereaaeeeuldbemerethen Eiiflifi'eminifialfimepeint. Itin
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`difliefltteh‘endferthemayefthepeatrefiigmflenemplesfiuemflm
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`analyfieulnflhudwfiafionandfllefaflm uffllesystmneuitahflitytesfingforfl—
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`heurfimepeinuamplee. Nevertheless, the decrease efaseayvalue efejrsteineis
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`netunexpeetedheaedenempefieuaexpaieneenfiththeapproveddrugms.
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`Additionallyfim amount efimpurity
`(b)(4)didnutinex'eaeeaiguifieanflyever
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`Wehhoughflmaevaheamfnrinfmmaflenanlydueteflmfafihneefflm
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`analytical mhudvalidnfiun. Moreover, eyeteinehyflmchlnride injeetiunhasa
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`lunghistoryufhumanusesineemproductfiemflesptewasapmvedinlflfle.
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`Therefomthesmdyremltureaeeepmhlefortehmendedpmpeee.
`Cysteine Assay Values {923
`EB]
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`# of Rep! mates
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`#efReplicates
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`RT: Room Temperature
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`4
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`Impurity:r
`0’) (4): Assay ‘34 H )
`Store at RT
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`#ef Rephcetea
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`RT: Room Temperature
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b)
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`(b) (4)
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`(b)
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`(b) (4)
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`Recommendation:
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`The PI and labels are now deemed satisfactory fiom the CMC perspective, and flora the
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`drug product perspective, the stability of the TPN admixture with Nouress is also deemed
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`acceptable, if it is kept under refrigeration up to 24 hours after mixing and being used
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`within 24 hours under room temperature.
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`Therefore, with the revised final PI and labels, and acceptable admixture stability data,
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`this application is now recommended for approval from the drug product and CMC
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`labeling perspectives.
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`Hong Cai, Ph.D.
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`Drug Product Reviewer
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`Branch IV, Division II, ONDP
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`Moo-Jhong Rhee, Ph.D.
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`Branch Chief
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`Branch IV, Division II, ONDP
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`Attachment-1:
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`Sections related to CMC in Prescribing Information submitted on December 11a
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`2019 SN0042 :
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`HIGHLIGHTS OF PRESCRIBING INFORlli-IATION
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`These highlights do not include all the information needed to use
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`NOURESS m safely and effectively. See full prescribing information for
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`NOURESS.
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`NOURESS (cysteine hydrochloride injection), for intravenous use
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`Initial [7.3. Approval: 1971
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`— DOSAGE FORMS AND STRENGTHS
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`Injection: 500 rag-"10 mL (50 mgfml) cysteine hydrochloride, USP in a
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`single-dose vial. (3)
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`Fu]l Prescribing Information:
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`Admixture Stability and Storage in Section 2.3
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`Stability and Storage
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`For single use only. Discard unused portion of the vial ofNOURESS.
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`0 Use parenteral nutrition solution containing NOURESS promptly after mixing. Any
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`storage of the admixture should be under refrigeration at 2°C to 8°C (36°F to 46°F) and
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`limited to a brief period of time. no longer than 24 hours. After removal from
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`refrigeration, inspect for precipitates, use promptly, and complete the infusion within 24
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`hours. Discard if any precipitates are observed.
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`0 Discard any remaining admixture.
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`o Protect parenteral nutrition solution from light.
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`3
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`DOSAGE FORNIS AND STRENGTHS
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`Injection: 500 trig/’10 mL (50 mg/mL) cysteine hydrochloride, USP as a clear. colorless, sterile
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`solution in a single-dose Vial.
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`11
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`DESCRIPTION
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`NOURESS (cysteine hydrochloride injection) is a sterile, nonpyrogenic solution for intravenous
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`use supplied as 500 mga’lo mL cysteine hydrochloride; USP in a single-dose vial.
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`Each ml. of NOURESS contains 50 mg of cysteine hydrochloride, (equixalent to 34.5 mg of
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`cysteine), and 0.006 ml. of hydrochloric acid (6M) in water for injection Sodium hydroxide
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`and’or hydrochloric acid are used as needed to adjust the pH. The pH range of NOURESS is 1.0
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`The active ingredient is cysteine hydrochloride. The chemical name of cysteine hydrochloride is
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`L-cysteine hydrochloride monohydrate. Its molecular formula is C3H1N025 0 HCI ' H20 and
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`molecular weight is 175.63. The chemical structure of L-cysteine hydrochloride monohydrate is
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`depicted below:
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`0
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`Cysteine hydrochloride is a white crystalline powder soluble in water. Cysteine is a sulfur-
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`containing more acid and is prone to oxidation when exposed to air in aqueous solution= which
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`may convert cysteine to insoluble cystine resulting in precipitation over time.
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`NOURESS contains no more than 143 mthL of aluminum
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`16
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`HOW SUPPLIEDISTORAGE AND HANDLING
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`NOURESS (cysteine hydrochloride injection} is a clear, colorless, sterile and nonpyrogenic
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`solution supplied as follows:
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`50!] tug-"1G mL (50 mgme} of cysteine hydrochloride, USP in single-dose 1rials {NBC T5014-
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`UUfi-US}, packaged as 5 vials per carton (NDC T6014-Dflfi-fli)
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`Store NOURESS at 20°C to 25°C {68°F to TWP); excursions permitted to 15°C to 30°C (59°F to
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`86 3F} [see USP Controlled Room Temperature]-
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`Protect from light. Avoid excessive heat. Protect from freezing. If accidentally frozen, discard
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`lVial stoppers are not made with natural rubber latex.
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`For storage of admixed solution see Dosage and Administration (2‘. 3,1
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`Manufacmred for:
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`Ayadel Legacy Pharmaceuticals, LLC
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`Chesterfield, MO ESGUE
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`Rey. 12.519
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`

`

`
`
`Attachment II:
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`-- ‘ .of the Carton nd Conta "er Labels submitted onDe
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`Carton. Labgl:
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`.C'ontainer-I 21a] Label):
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`(b) (4)
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`(b) (4)
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`

`

`/-\ Hong
`Cai
`
`/'\Moo Jhong
`SiRhee
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`Digitally signed by Hong Cai
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`Date: 12/11/201911:33:58AM
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`GUID: 55919d6500e16bdaad5825645e4f22ff
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`Digitally signed by Moo Jhong Rhee
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`Date: 12/11/2019 11:41 :4OAM
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`GUID: 502d0913000029f979803689a802fa55
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`
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`

`

`
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`Digitally signed by Hitesh Shroff
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`Date: 12/12/2019 04:05:14PM
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`GUID: 502d1ab500002afd219fd67e3b9099c8
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`

`

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`QUALITY ASSESSMENT
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`Recommendation: As ofthis review,this 505 (b)(2) NDA is not ready for Appro§fi~fi..ifi
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`present form per 21 CFR 314.125(b)(6).
`
`NDA 212535
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`OPQ Review #1
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`Drug NamefDosage Form
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`Strength
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`Route of Administration
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`RXIOTC Dispensed
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`Applicant
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`US agent, if applicable
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`Cysteine Hydrochloride Injection, for intravenous use
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`500 mg/lOmL(50 mg/mL)
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`Injection
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`Flamel Ireland Limited dba Avadel Ireland, Ireland
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`Marla Searola, The Weinberg Group, Washington, DC
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`DISCIPLINE(S) AFFECTED
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`DOCUMENT
`SUBMISSIONS)
`REVIEWED
`DATE
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`———_
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`mm—
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`——n_
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`——_n_
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`——“
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`———_
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`——-m_
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`——-n_
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`——-n_
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`———_
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`—-:E_
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`———r_
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`——__
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`——_n_
`——-:E_
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`———n_
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`—-n_
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`—_m_
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`———n_
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`m—
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`m—
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`

`

`QUALITY ASSESSMENT
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`Quality Review Team
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`DISCIPLINE
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`esteem
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`Pmcessmmmaes
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`meioloav
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`Regulatory Business
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`REVIEWER
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`mmmmm
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`mm
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`Quality Review Data Sheet
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`Status
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`A .
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`om
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`Dec 11, 2015
`indications 0 Reference Listed Drug (RLD):
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`Cysteine Hydrochloride Injection, 72
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`mg/mL from Hospira 1110., 11.
`0 Discontinued on Jun 6, 2006 for
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`reasons other than safety and
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`eflicacy
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`B. Other Documents: M. RLD, or sister . . fictitious
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`NBA
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`019523
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`Reviewed by Lawrence
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`Active Notreviewed,
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`Oct 17, 2018
`
`LOA
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`From the same applicant and for same
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`
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`QUALITY ASSESSMENT
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`2. CONSUi'I-Sé None
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`DISCIPLINE
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`STATUS
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`—_—-—
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`—_—-—
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`—_—-—
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`m———-—
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`RECOMMENDATION
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`DATE
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`REVIEWER
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`

`

`QUALITY ASSESSMENT
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`
`
`Executive Summary
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`1.
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`Recommendations and Conclusion on Approvability
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`The applicant has provided adequate CMC information to assure the identity,
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`strength, purity, and quality of the proposed Nouress (cysteine hydrochloride
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`injection) 500 rug/10 mL (50 mg/mL).
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`The claim for the Categorical Exclusion for the Environmental Assessment is
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`granted.
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`The Office of Process and Facilities (OPF) has made a final overall “Approval”
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`recommendation for the facilities involved in this application.
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`The label/labeling issues have not been satisfactorily resolved as of this review.
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`Therefore, from the OPQ perspective, this NDA is not deemed ready for approval in
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`its present form per CFR 314.125(b)(6). until above mentioned issues are
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`satisfactorily resolved. (see the List of Deficiencies)
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`II. Summary of Quality Assessments
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`A. Product Overview
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`Nouress (cysteine hydrochloride injection) 500 mg/10 mL (50 mg/mL) is a sterile,
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`nonpyrogenic solution for intravenous use. Each 10 mL ofNouress contains 500 mg
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`of Cysteine Hydrochloride, USP
`t” “”1111. of hydrochloric acid
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`(6 Molar) in Water for Injection, USP. The pH of the solution is adjusted to 1.0 to 1.5
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`with hydrochloric acid or sodium hydroxide. There are no preservatives or anti-
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`oxidants in this formulation.
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`(b) (4)
`(b) (4)
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`Nouress is supplied as a single-dose vials. Nouress must be diluted and used as an
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`admixture in parenteral nutrition solutions.
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`Nouress
`Proposed Indication(s) including
`4
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`('3) (
`)indicated for use as an
`Intended Patient Population
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`additive to amino acids sohrtions to meet nutritional requirements
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`of neonates (preterm and term infants less than one month of age)
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`requiring total parenteral nutrition.
`Duration of Treatment
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`(b) (4)
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`Maximum Daily Dose o The recommended dosage in neonates is based upon the
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`recommended daily protein (amino acid) requirements: 22 mg
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`NOURESng amino acids. The corresponding volume is 0.44 mL
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`NOURESng amino acids.
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
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`

`

`QUALITY ASSESSMENT
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`Ns’A
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`Alternatlve Methods of Administration
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`B. Quality Assessment Overview
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`Drug Substance: The active ingredient in Nouress (cysteine hydrochloride injection)
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`500 mg! lOrnL1s L-cysteine hydrochloride monohydrate. The drug substanceis a white“
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`crystalline powder. It1s hygroscopic and very solublein water
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`Cysteine hydrochloride monohydrate1s a natural amino acid. Itis a chiral naturally
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`occurring amino acid with a molecular weight of 175.63 g/mol and a molecular formula
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`of C3H7NOzS.HCl.HzO.
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`C?
`|
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`HS
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`NH2
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`0H
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`
`. HCI . H20
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`(b) ‘4) under cGMP
`Manufacturing: It is manufactured by
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`conditions
`(b) (4).. The complete CMC information regarding
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`raw materials, manufacturing, purification, characterization, stability, storage and
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`container closure is provided in DMF
`(b) (4% A Letter of Authorization was also
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`submitted by the manufacturer.
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`The overall quality of L-cysteine hydrochloride monohydrate is controlled by its
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`specification, which includes appearance, identification test
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`(b) ‘4)
`(b) (4)
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`The drug substance meets the USP specification. The biopharmaceutical classification
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`(BCS), particle size and polymorphism of the drug substance are not important because
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`the drug product is an injection for intravenous administration.
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`The applicant provided satisfactory certificates of analysis of four batches of the drug
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`substance usedin the manufacture ofthe drug product. The proposed re-test period of
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`Wdeemed acceptable. The DMF
`(b) was reviewed by Dr. Lawrence Perez
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`and was deemed adequate from the CMC perspective. (See the Drug Substance
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`review)
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`(b) ‘4)
`The API, L-cysteine hydrochloride monohydrate, manufactured by
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`‘4) is controlled to conform to the requirements (specification)
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`to produce Nouress (cysteine hydrochloride injection) 500 mg] 10mL.
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`Drug Product: Nouress (cysteine hydrochloride injection) 500 mg/10 mL (50 mg/mL)
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`is clear, colorless, sterile and nonpyrogenic solution. Each mL of the drug product
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`contains 50 mg of L-cysteine hydrochloride monohydrate (equivalent to 34.5 mg of L-
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`cysteine). The pH range of the drug product is 1.0 to 1.5. The drug product is not for
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`direct intravenous infusion, it must be diluted and admixed with a TPN solution prior to
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`intravenous administration. As there are no preservatives or anti-oxidants in the drug
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`product formulation, it is a single-dose drug product and the unused portion should be
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`discarded The drug product is supplied 3510 mL USP
`(b) “”2 clear glass vial, closed
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`with a stopper and sealed with a brown flip-off cap.
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`(b) (4)
`
`

`

`QUALITY ASSESSMENT
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`The drug product specification includes appearance, identity tests, assay for strength,
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`impurities by validated HPLC methods as well as bacteria] endotoxin per USP <85> for
`
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`purity; pH, particulate matter per USP <788>, extractable volume per USP <697>,
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`aluminum content tests for quality and sterility per USP <71>. The elemental impurities
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`per USP <232>, USP <233> and ICH Q3D are not included in the drug product
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`specification because no elemental impurities were detected above 8% of PDE in
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`historical batches.
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`The drug product strength is the only difference between the reference listed drug (LD)
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`fi'om Hospira (72.5 mg/mL) and the proposed drug product (50 mg/mL). Due to the lower
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`strength of the proposed drug product, a slightly larger volume is required compared to
`
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`the LD to achieve the same amount of cysteine in the admixture. Based on the
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`comparative physico—chemical properties of the to-be administered dosage form, the FDA
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`determined that a biobridge has been established between the proposed and the listed
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`drug product as per 21 CFR 320.24 (b)(6) to assure similar inn-viva disposition of
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`cysteine. Thus, an additional in vivo bioequivalence (BE) bridging study is not needed.
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`(see the Biopharmaceutics review)
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`The Cysteine Hydrochloride Injection compatibility study was conducted with commonly
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`used in typically used TPNs and diluents e.g. 10% Dextrose Injection, TrophAmine,
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`Calcium Gluconate Injection and Potassium Phosphate Injection. In the compatibility
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`study, appearance, pH, osmolality, viscosity, assay, related substances, particulate matter
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`and in-use stability were assessed. The admixtures appear to be stable up to 24 hours at
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`25°C, but some particulate matters were observed when, afier admixing, it was stored at
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`5°C. Based on this observation, it was recommended not to refiigerate after admixing of
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`this product, unless admixed with just nutritional TPN
`(b) (4):.
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`The stability testing of the drug product batches was performed in accordance with ICH
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`Q3A(R2). Based on the satisfactory 12-month long-term stability in upright and inverted
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`positions at 25°C and 6-month accelerated stability data at 40°C fi’om three primary
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`registration batches, the proposed 24-month of expiration dating period is granted when
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`stored at 25°C in the proposed container closure system. (see the Drug Product review).
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`Manufacturing:
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`Nouress (cysteine hydrochloride injection) 500 mg]10 mL (50 mg/mL) is manufactured,
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`tested and released by
`(b) (4).. The manufacturing
`('3) (4).
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`process involves
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`(b)
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`(b) (4)
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`(b) (4)
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` QUALITY ASSESSMENT
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`This NDA is recommended for approval based
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`on drug product sterility assurance from the microbiological perspective. (See the
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`Microbiology review)
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`Facilities:
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`The Office of Process and Facilities (OPF) has made an “Adequate” recommendation for
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`all drug substance and drug product manufacturing and testing facilities. (See the
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`Manufacturing Integrated Assessment review)
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`Environmental Assessment:
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`In accordance with 21 CFR 25.15(d), Avadel affirms that the requested action, approval of
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`the NDA for Cysteine Hydrochloride Injection, USP qualifies for a categorical exclusion
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`fiom the requirement to prepare an environmental assessment under 21 CFR 25.3 1(a).
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`Action on the NDA will not increase the use ofthe active moiety. In addition, to the
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`applicant’s knowledge there are no extraordinary circumstances indicating that the
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`proposed action would significantly affect the quality ofthe human environment (21 CFR
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`25.21).
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`Therefore, claim of a categorical exclusion from the requirements of an environmental
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`assessment (EA) in accordance with 21 CFR Part 25.3 1(a) and 21 CFR Part 25.15 (d),
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`was deemed acceptable. (See the Drug Product review)
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`Labeling: As of this review, the labels and labeling issues are not satisfactorily resolved
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`from the CMC perspective according to the labeling/label review. (See the List of
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`Deficiencies below and Labeling review).
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`C. Post Approval Commitment: None
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`D. Lifecyele Management Considerations: None
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`E. Special Product Quality Labeling Recommendations: None
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`F. Final Risk Assessment (see Attachment)
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`G. List of Deficiencies:
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`The following labeling deficiencies should be resolved with the applicant:
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`A. Regarding Labels
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`For the leflml vial carton label:
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`1. Provide the lot number and expiration date information on the carton label.
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`2.
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`Include “See package insert for the dosage information” on the carton label.
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`(b) (4)
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`(b) (4)
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`

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`45 Page(s) has been Withheld in Full as b4 (CCI/TS) immediately following this page
`
`

`

`QUALITY ASSESSMENT
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`
`
`CHAPTER IV: LABELING
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`1.0 PRESCRIBING INFORMATION
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`1.1 Highlights of Prescribing Information
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`HIGHLIGHTS OF PRESERJBDEG MDRhi-EHUN
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`These highlights do not include all the informationneeded to use
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`(b) (4)"$afe1}' and archival}: see full-prescribing '
`(b) (4)..
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`information for
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`(b) Wu [gwmme Wimhlflw, _
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`Mgigttiogr- (b) (‘9ng mu‘arflmuggg
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`Initial L15. Approval: 1971
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`.
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`a
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`4
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`DOSAGE FOREIS :L‘N'D STRENGTHS
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`(b) Mlsinaleflose‘” (4) rial
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`Product Title (Labeling Review Tool and 21 CFR
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`.2__9_L§__7__(_§)_Q))_____________________________________
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`Proprietary name and
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`established name
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` Hydrochloride Injection, USP) Revise the product title to one(b) (4)
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`Not Satisfactory
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`of the following formats:
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`Once the format is selected,
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`the entire PI document should
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`be revised to have the
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`consistent format for the
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`presentation of established
`name.
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`“Tradename (cysteine
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`hydrochloride) Injection, for
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`intravenous use” or
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`“Tradename (cysteine
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`hydrochloride injection), for
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`intravenous use”.
`
`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

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`
`QUALITY ASSESSMENT
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`Dosage Forms and Strengths (Labeling Review Tool and 21
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`§_E_51S__2_Q_1__-_§_7__@2_(§))________________________________________________________________________________________
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`Summary of the dosage form
`Not Satisfactory
`(b) (4)
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`and strength
`Revise to:
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`“Injection: 500 mg/ 10 mL
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`(50 mg/mL) cysteine
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`hydrochloride, USP in a
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`le-dose vial .”
`(b) ‘4)
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`*Cysteine Hydrochloride is defined in USAN as a monohydrate substance.
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`(b) (4)
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`1.2 Full Prescribing Information
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`1.2.1 Section 2 (Dosage and Administration)
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`Note: Only the following content in Section 2.3 related to storage condition of the admixture will be reviewed.
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`Stability and Storage
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`For single use only. Discard used container of
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`The amino acids admixture should be refrigerated until ready for use and used within 24 hours of
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`the time of mixing.
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`(b) (4)
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`Use
`(b) (4) fillxmg. Any storage of the admixture
`solution containing
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`should be under refrigeration and limited to a brief period of time. no longer than 24 hours. After
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`removal from refrigeration. use promptly and complete the infusion within 24 hours. Discard any
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`remaining admixture.
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`Protect
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`8% solution from light.
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`tem
`Information Provided in NDA Reviewer’s Assessment
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`_(Refer to Labeling Review Tool and 21 CFR 201.57(c) 02))
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`Special instructions for [W
`(b) (4)
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`product preparation (e.g.,
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`reconstitution, mixing with
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`food, diluting with
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`compatible diluents)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b)
`(4)
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`(b) (4)
`
`

`

`
`QUALITY ASSESSMENT
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`3
`DOSAGE FORMS AND STRENGTHS
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`11.1:g11u;=.._ jun; :21: 15:1111l_l_i§LJ mg ml; Lifiuifilpfidiotiluigoi.L31“ 31;. a Heagolo'leh lit-Ellie H
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`aiiuiiill, 1;; 9,
`$31
`1.12:2: __
`(b) “”-
`-
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`(b) (4)
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`Item
`Information Provided in NDA Reviewer’s Assessment
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`(Refer to Labeling Review Tool and 21 CFR 201.57(c)(4))
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`Available dosage forms
`Not provided
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`Strengths: in metric system
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`50 mg/mL
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`A description of the identifying Not provided.
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`characteristics of the dosage
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`forms, including shape, color,
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`coating, scoring, and
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`imrintin_, when a licable.
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`1.2.3 Section 11 (Description)
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`Not Satisfactory
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`Add the dosage form
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`“In’ection” .
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`Not Satisfactory
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`The strength of the total
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`content in the vial is not
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`defined.
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`The strength is not clearly
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`defined as “cysteine
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`hydrochloride”.
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`Revise to
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`“500 mg/ 10 ml (50 mg/mL)
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`cysteine hydrochloride as a
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`clear, colorless, sterile
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`solution in a
`(b) ‘4) single-
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`dose vial.”
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`Not Satisfactory
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`See the revision comment in
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`the section “Strengths: in
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`metric system”.
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`(b)
`(4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`(b) (4)
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`

`

`
`QUALITY ASSESSMENT
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` Information Provided in NDA
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`(Refer to Labeling Review Tool and 21 CFR 201 57(0) (12),