Case 1:20-cv-00024-MN Document 1-1 Filed 01/07/20 Page 2 of 4 PageID #: 25
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`DEPARTMENT OF HEALTH AND HUMAN SERVICES
`
`Food and Drug Administration
`Silver Spring MD 20993
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`GENERAL ADVICE
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`NDA 210660
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`Exela Pharma Sciences, LLC
`Attn: Aruna Koganti
`Executive Director of Clinical and Regulatory Affairs
`P.O. Box 818
`1245 Blowing Rock Blvd.
`Lenoir, NC 28645
`
`Dear Dr. Koganti:
`
`Please refer to your New Drug Application (NDA) submitted under section 505(b) of the Federal
`Food, Drug, and Cosmetic Act for L-Cysteine Hydrochloride Injection, USP, 50 mg/mL.
`
`We also refer to your May 23, 2017, submission, containing the first portion of your NDA
`rolling review and your July 26, 2017 response to an information request from Oumou Barry,
`MHA, MT, ASCP, Lieutenant Commander, US Public Health Service, Regulatory Business
`Process Manager, Office of Program and Regulatory Operations, Office of Pharmaceutical
`Quality, Center for Drug Evaluation and Research.
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`We have reviewed the referenced material and have the following recommendations:
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`Based on our previous experience with small volume parenteral drug products used in TPN, we
`have determined that the aluminum dose delivered by your drug product, L-Cysteine
`Hydrochloride Injection, 0.5g/10mL, should be limited to ≤ 0.6 mcg/kg/day. To comply with
`this dose level, a limit of ≤ 145 mcg/L aluminum is needed. The limit of 145 mcg/L for
`aluminum concentration in your drug product is derived based on the maximum dose of total
`amino acid at 3.5 gram/kg/day with 40 mg/gram of amino acid of L-cysteine added. Current
`clinical recommendations for total amino acid doses range from 0.5 to 3.5 gram/kg/day, and 20
`to 40 mg of L-cysteine is required for each gram of amino acid in the final TPN infusion
`solution.
`
`You have indicated that you intend to change the primary container closure from the glass vials
`to plastic vials in an attempt to reduce and control the level of aluminum in the drug product at
`release and throughout the desired product shelf-life. We remind you that this change will
`require full assessment of the proposed container closure leachables/extractables as well as
`toxicological evaluation of the potential leachable compounds. See our recommendations for
`safety assessment of leachables/extractables in the meeting minutes for PIND 128489 dated
`December 23, 2015. Additionally, container closure integrity must be established during
`accelerated and long-term stability to ensure that it is capable of protecting the drug product from
`its external environment and maintaining the drug product sterility throughout the proposed
`product shelf-life.
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`Reference ID: 4134991
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`Eton Ex. 1019
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`Case 1:20-cv-00024-MN Document 1-1 Filed 01/07/20 Page 3 of 4 PageID #: 26
`NDA 210660
`Page 2
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`The primary container closure information must include material description and specification
`for each component of the proposed container closure system, the DMF number for each
`component, and the letter of authorization for the review of each referenced DMF. Regardless of
`whether the new container closure components have been accepted by the Agency for use in
`approved drug products, a thorough safety assessment of leachables/extractables will be needed
`due to the extremely low pH range (1-2.5) for your product.
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`We strongly recommend that you maintain communication with the Agency CMC review team
`to keep us informed on your progress and evolving strategy to resolve the concern about
`aluminum levels in the drug product. In addition to the information provided in PIND 128489
`meeting minutes about the safety assessment of leachables/extractables, the Division’s
`nonclinical team can provide further guidance as needed, and respond to your questions in order
`to facilitate the completion of the required safety assessment.
`
`If you have any questions, call Evangela Covert, Regulatory Project Manager, at (301) 796-4075.
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`Sincerely,
`
`{See appended electronic signature page}
`
`Donna Griebel, M.D.
`Director
`Division of Gastroenterology and Inborn Errors
`Products
`Office of Drug Evaluation III
`Center for Drug Evaluation and Research
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`Reference ID: 4134991
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`This is a representation of an electronic record that was signed
`electronically and this page is the manifestation of the electronic
`signature.
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`/s/
`----------------------------------------------------
`DONNA J GRIEBEL
`08/04/2017
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`Reference ID: 4134991
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