CENTER FOR DRUG EVALUATION AND
`RESEARCH
`
`APPLICATION NUMBER:
`
`218808Orig1s000, 218820Orig1s000
`
`PRODUCT QUALITY REVIEW(S)
`
`1
`
`NEUROCRINE-1054
`
`

`

`RECOMMENDATION
`(cid:1800) Approval
`
`(cid:1407) Approval with Post-Marketing Commitment
`(cid:1407) Complete Response
`
`NDA 218808
`Assessment # 1
`
`CRENESSITY (Crinecerfont)
`Capsule
`25 mg, 50 mg, 100 mg
`Oral
`Rx
`Neurocrine Biosciences Inc.
`N/A
`
`(b) (4)
`
`N/A
`200 mg/day
`None
`
`Drug Product Name
`Dosage Form
`Strength
`Route of Administration
`Rx/OTC Dispensed
`Applicant
`US agent, if applicable
`Proposed Indication(s)
`including Intended Patient
`Population
`
`Duration of Treatment
`Maximum Daily Dose
`Alternative Methods of
`Administration
`
`Submission(s)
`Assessed (eCTD
`Sequence)
`
`0001
`0005
`0006
`0009
`0010
`0013
`
`Document Date
`
`Discipline(s) Affected
`
`04/29/2024
`06/14/2024
`06/18/2024
`07/08/2024
`07/16/2024
`08/26/2024
`
`Quality (Original NDA submission)
`Quality
`Quality
`Quality
`Quality
`Quality
`
`Reference ID: 5458594
`
`2
`
`

`

`QUALITY ASSESSMENT TEAM
`
`Secondary Assessor
`Primary Assessor
`Zhengfu Wang
`Stephanie Springer
`Akm Khairuzzaman
`George Ward
`Aditi Thakur
`Kejun Cheng
`Haritha Mandula
`Rajesh Savkur
`Akm Khairuzzaman
`George Ward
`Oluwafunmike Ajomale
`
`Akm Khairuzzaman
`
`Discipline
`Drug Substance
`Drug Product
`Manufacturing
`Biopharmaceutics
`Environmental
`Regulatory Business
`Process Manager
`Application Technical
`Lead
`
`
`
`
`
`
`Reference ID: 5458594
`
`3
`
`

`

`QUALITY ASSESSMENT DATA SHEET
`
`1. RELATED/SUPPORTING DOCUMENTS
`
`A. DMFs: Acceptable.
`
`DMF No. Type
`
`Holder
`
`(b) (4)
`
`IV
`
`III
`
`III
`
`III
`
`Item
`Referenced
`(b) (4)
`
`Status
`
`Comments
`
`Active
`
`Adequate
`
`Active
`
`Adequate
`
`Active
`
`Active
`
`Adequate
`
`Adequate
`
`B. OTHER DOCUMENTS: IND, RLD, RS, Approved NDA
`
`None
`
`The Office of Pharmaceutical Quality Research (OPQR), OPQ was
`2. CONSULTS
`consulted for analytical method verification.
`
`Reference ID: 5458594
`
`4
`
`

`

`EXECUTIVE SUMMARY
`
`
`I. RECOMMENDATIONS AND CONCLUSION ON APPROVABILITY
`
`From the chemistry, manufacturing, and controls (CMC) perspective, NDA 218808 is
`recommended for approval. As part of this action, an expiration period of 15 months for
`the product, stored at 15°C - 25°C (59(cid:101)F to 77(cid:101)F) in the commercial packaging, is
`granted.
`
`
`II. SUMMARY OF QUALITY ASSESSMENTS
`
`In accordance with section 505(b)(1) of the Federal Food, Drug and Cosmetic Act, the
`applicant Neurocrine Biosciences Inc., submitted NDA 218808 to seek marketing
`approval for CRENESSITY™ (crinecerfont) capsule, for oral use. Crinecerfont is a new
`chemical entity (NME). Its identity, purity, impurity, and manufacturing are adequately
`controlled through appropriate quality management system and validated analytical
`methods. The drug substance is stable for the intended storage period in its commercial
`packaging system. The new drug product is an oral soft gel capsule formulated with
`excipients such as: medium-chain triglycerides, propylene glycol dicaprylate/ dicaprate ,
`lauroyl polyoxyl-32 glycerides, and vitamin E polyethylene glycol succinate. Note that
`propylene glycol dicaprylate has not been used in any oral products before but its
`quantitative level used in the formulation is found to be acceptable by the Pharm/tox
`reviewer. The drug product is supplied in three different strengths (25 mg, 50 mg and
`100 mg), packed in a HDPE bottle with child resistant cap. The manufacturing process
`is adequately controlled by the quality management system of the listed cGMP
`compliant manufacturing facilities. From a quality perspective, the proposed control
`strategies are adequate to ensure consistent product quality with regard to identity,
`strength, purity, potency, and stability.
`
`
`
`A. Quality Assessment Overview
`
`Drug Substance: Adequate
`Crinecerfont, a new synthetic small molecule that has one stereocenter in the S
`configuration. Sufficient characterization is provided to assure the identity and purity of
`the drug substance. The drug substance structure has been characterized adequately
`using 1H NMR, 13C NMR, elemental analysis, FTIR, MS, and single crystal X-ray
`structure determination. Absolute configuration of the stereocenter is confirmed by X-
`ray crystal structure. The commercial manufacturing process yields the drug substance
`as a single polymorph
` The drug substance is BCS Class 4. However, particle
`size and polymorphism of the drug substance are not critical
`
`
`(b) (4)
`
`(b) (4)
`
`Reference ID: 5458594
`
`5
`
`

`

`(b) (4)
`
` The applicant has
`used the well-established synthesis for manufacture of the drug substance which
`adequately controls residual solvents, elemental impurities, and mutagenic impurities
`as per the applicable ICH guidance. Starting materials are appropriately designated.
`The drug substance quality control specification includes relevant quality attributes such
`as description, identification by FTIR and HPLC, assay, chiral purity, water content,
`organic impurities, and microbial limits. Analytical methods to control the quality of the
`drug substance are adequate and appropriately validated. Stability data support the
`proposed re-testing period of months when stored
` For additional information, please refer to Dr. Stephanie Springer’s
`review in Panorama dated 08/8/2024.
`
`(b) (4)
`
`(b) (4)
`
`Drug Product: Adequate
`Crinecerfont capsule is formulated with excipients such as: medium-chain triglycerides
`(b) (4)
`(b) (4)
`propylene glygcol dicaprylate/dicaprate
` lauroyl polyoxyl-32
`(b) (4)
`(b) (4)
` and vitamin E polyethylene glycol succinate
`
`glycerides
`
`(b) (4)
`
`(b) (4)
` The quantitative level of the novel excipient (i.e.,
`propylene glycol dicaprylate) in the formulation is found to be adequate from pharm/tox
`(b) (4)
`as well as from CMC perspective. There are
` in the product
`formulation and there is no change in the formulation composition between the
`commercial product and the Phase 3 trial product.
` particle size of the drug substance is not expected to
`impact the product quality. During the product development, critical quality attributes
`were identified, and they are adequately controlled by product specification which
`includes tests for description, identification, assay, degradation products, dissolution,
`uniformity of dosage units, and microbial attributes. All analytical methods for quality
`control of the product are adequate and they are appropriately validated. Based on the
`provided stability data, the Applicant’s proposed shelf-life of 15 months is acceptable
`when stored at 15°C - 25°C (59(cid:101)F to 77(cid:101)F). However, Dr. Ward’s review mentions
`tha
`
`(b) (4)
`
`(b) (4)
`
` The drug product is supplied in a 120cc HDPE bottle with a 38mm child resistant
`cap and foil seal over the bottle opening. For additional information, please refer to Dr.
`George Ward’s review in Panorama dated 10/07/2024.
`
`Labeling: Adequate
`Updated labeling information is found to be adequate by the chemistry reviewer, Dr.
`George Ward. Minor edits were made in the chemistry section of the package insert.
`
`Reference ID: 5458594
`
`6
`
`

`

`Manufacturing: Adequate
`The drug product is manufactured
`
`(b) (4)
`
` The batch
` The manufacturing process reviewer, Dr.
`size for the is
`Kejun Cheng concludes that the manufacturing process is adequately controlled by
`appropriate control strategy, including in-process controls.
`
`(b) (4)
`
` Biopharmaceutics: Adequate
`The biopharmaceutics reviewer, Dr. Rajesh Savkur concludes that crinecerfont, a
`poorly soluble drug,
`
`
`
`(b) (4)(b) (4)
`
` For quality control purpose, the Applicant’s proposed two-
`tier dissolution method is found to be adequate, and the overall biopharmaceutics risk is
`low. Dr. Savkur also concludes that the capsule fill formulation of the three strengths is
`compositionally proportional to each other. Based on the totality of the information and
`data submitted in support of the bridging across the formulations, additional strengths,
`manufacturing sites and batch sizes, a waiver for demonstration of in vivo
`bioequivalence for the 25 mg and 50 mg strengths of the “to be marketed” formulation
`is found to be acceptable as per the 21 CFR 320.22(d)(2). No additional in vivo study is
`required.
`
` Manufacturing Facilities: Adequate
`
`Based on the inspection history, manufacturing experience and acceptable compliant
`status, the Office of Pharmaceutical Manufacturing Assessment (OPMA) has
`recommended an overall approval for all the currently listed manufacturing and testing
`facilities concerning this NDA.
`
`Reference ID: 5458594
`
`7
`
`

`

`B. Risk Assessment: Overall quality risk is low.
`
`CQAs
`
`Assay (API),
`stability
`
`Initial
`Risk
`Ranking
`
`Medium to
`Low
`
`Comments
`
`Updated Risk
`Ranking after
`Assessment
`Cycle #
`
`(b) (4)
`
`Low
`
`Comments
`
`(b) (4)
`
`Physical stability
`(solid state)
`
`Low
`
`Degradation
`impurities
`
`Medium to
`low
`
`Dissolution
`
`Medium to
`Low
`
`Microbial limits
`
`Low
`
`Content uniformity
`
`Low
`
`Low
`
`Low
`
`Low
`
`Low
`
`Low
`
`C. List of Deficiencies for Complete Response:
`None
`
`Application Technical Lead Name and Date:
`
`Akm Khairuzzaman, Ph.D. 10/07/2024
`
`65 Page(s) have been Withheld in Full
`as b4 (CCI/TS) immediately following
`this page
`
`Reference ID: 5458594
`
`8
`
`

`

`CHAPTER IV: LABELING
`
`NDA Number
`Assessment Cycle Number
`Drug Product Name
`
`NDA 218808
`#1
`CRENESSITY / Crinecerfont soft gel capsule
`
`Assessment Recommendation: Adequate
`
`Item
`
`Assessment Conclusion
`
`Prescribing Information
`Labeling
`Patient Information
`Instruction for Use (IFU)
`Container Labels
`Carton Labeling
`
`Adequate
`
`Adequate
`Adequate
`Adequate
`Adequate
`
`SDN # where labeling is
`adequate (“N/A”
`otherwise)
`0001
`
`0001
`0001
`0001
`0001
`
`Brief Description of Outstanding Issues: None
`
`Submissions being reviewed:
`Document Reviewed
`Date Received
`(eCTD #, SDN #)
`0001, 1
`
`4/29/2024
`
`Information Provided
`
`Initial NDA Package
`
`1.0 PRESCRIBING INFORMATION1
`
`Assessment of Product Quality Related Aspects of the Prescribing Information:
`
`1 Labeling Review Tool (LRT) (March 2022), including use of consistent terminology for dosage form and unit
`of measure for strength in the product title and DOSAGE FORMS AND STRENGTHS heading in Highlights,
`in the DOSAGE AND ADMINISTRATION, DOSAGE FORMS AND STRENGTHS, DESCRIPTION, and HOW
`SUPPLIED/STORAGE AND HANDLING sections (see page 2 of LRT)
`
`Reference ID: 5458594
`
`9
`
`

`

`1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION
`
`(b) (4)
`
`Item
`
`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`Product Title in Highlights2 [21 CFR 201.57(a)(2)]
`Established name(s)3
`Adequate
`
`Adequate
`N/A
`
`Assessor’s Comments
`(If an item is Inadequate, provide more details on
`the issues, as appropriate)
`
`The proposed name, CRENESSITY®
`(crinecerfont) capsules, for oral use is
`adequate.
`Route of administration is in the title.
`Not a controlled drug substance.
`
`Route(s) of administration
`Controlled drug substance
`symbol (if applicable)
`Initial U.S. Approval
`[§201.57(a)(3)]
`Dosage Forms and Strengths Heading in Highlights [§ 201.57(a)(8)]
`Dosage form(s)4 and
`Adequate
`Dosage form: Capsules
`strength(s) in metric system5
`Strength: 25, 50, and 100 mg
`
`Adequate
`
`Adequate.
`
`2 Draft guidance: Product Title and Initial U.S. Approval in the Highlights of Prescribing Information for Human
`Prescription Drug and Biological Products — Content and Format (January 2018)
`3 Established name = [Drug] [Route of Administration] [Dosage Form]. Do use not “USP” descriptor in the
`product title or within the Highlights (see page 3 of LRT).
`4 Draft guidance: Product Title and Initial U.S. Approval in the Highlights of Prescribing Information for Human
`Prescription Drug and Biological Products — Content and Format (January 2018); USP <1151>; USP
`Nomenclature Guideline
`5 Labeling Review Tool (March 2022, page 13), include limited packaging information; USP <7>
`
`Reference ID: 5458594
`
`10
`
`

`

`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`N/A
`
`Assessor’s Comments
`(If an item is Inadequate, provide more details on
`the issues, as appropriate)
`
`Not a salt.
`
`N/A
`
`Not a tablet.
`
`N/A
`
`Not an injectable product.
`
`Item
`
`If the drug product contains
`an active ingredient that is a
`salt, clearly state whether
`the strength is based on the
`active moiety (e.g., Tablets:
`10 mg of drug-x) or active
`ingredient (e.g., Tablets: 10
`mg of drug-x
`hydrochloride).6
`Assess if the tablet is
`scored. If product meets
`guidelines and criteria for a
`scored tablet, state
`“functionally scored.”7
`For injectable drug products
`for parenteral administration,
`use appropriate package
`type term (e.g., single-dose,
`multiple-dose, single-patient-
`use). Other package terms
`include pharmacy bulk
`package and imaging bulk
`package.8
`
`
`Assessment: Adequate
`
`The highlights of prescribing information is acceptable from Drug Product’s perspective.
`
`
`
`
`
`6 Guidance: Naming of Drug Products Containing Salt Drug Substances (June 2015); MAPP 5021.1
`7 Guidance: Tablet Scoring: Nomenclature, Labeling, and Data for Evaluation (March 2013)
`8 Guidance: Selection of the Appropriate Package Type Terms and Recommendations for Labeling Injectable
`Medical Products Packaged in Multiple-Dose, Single-Dose, and Single-Patient-Use Containers for Human
`Use (October 2018); USP <659>
`
`Reference ID: 5458594
`
`11
`
`

`

`1.2 FULL PRESCRIBING INFORMATION
`
`1.2.1 Section 2 (DOSAGE AND ADMINISTRATION)9
`
`(b) (4)
`
`Item
`
`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`DOSAGE AND ADMINISTRATION section
`Special instructions for product
`N/A
`preparation (e.g., reconstitution
`and resulting concentration,
`dilution, compatible diluents
`and/or soft food10, storage
`conditions needed to maintain
`the stability of the reconstituted
`or diluted product).
`Important administration
`instructions supported by product
`quality information (e.g., do not
`crush or chew extended-release
`tablets, instructions for mixing
`with food).
`For parenteral products: include
`statement: “Parenteral drug
`
` Adequate
`
` N/A
`
`Assessor’s Comments
`(If an item is Inadequate, provide more details
`on the issues, as appropriate)
`
`No special instructions for product
`preparation.
`
`Administration information is adequate
`and supported by the product quality
`information.
`
`Not a parenteral product.
`
`9 See § 201.57(c)(3); draft guidance: Dosage and Administration Section of Labeling for Human Prescription
`Drug and Biological Products — Content and Format (January 2023); Labeling Review Tool (March 2022,
`page 25)
`10 Draft Guidance: Use of Liquids and/or Soft Foods as Vehicles for Drug Administration: General
`Considerations for Selection and In Vitro Methods for Product Quality Assessments
`
`Reference ID: 5458594
`
`12
`
`

`

`Item
`
`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`
`Assessor’s Comments
`(If an item is Inadequate, provide more details
`on the issues, as appropriate)
`
`products should be inspected
`visually for particulate matter and
`discoloration prior to
`administration, whenever
`solution and container permit.”11
`If there is a USP monograph for
`the drug product and it contains
`a labeling requirement, ensure
`the labeling requirement is
`fulfilled.12 Note the labeling
`requirement may be applicable
`to another section of the PI (e.g.,
`Section 11).
`For radioactive products, include
`radiation dosimetry for the
`patient and healthcare
`practitioner(s) who administer
`the drug
`For hazardous products, include
`the statement “DRUG X is a
`hazardous drug. Follow
`applicable special handling and
`disposal procedures.x” with x
`numerical citation to “OSHA
`Hazardous Drugs.”
`
`Assessment: Adequate
`
`Section 2 is adequate
`
` N/A
`
`No USP labeling requirement.
`
` N/A
`
`Not a radioactive product.
`
` N/A
`
`Not a hazardous product.
`
`1.2.2 Section 3 (DOSAGE FORMS AND STRENGTHS)13
`
`(b) (4)
`
`11 §201.57(c)(3)(iv)
`12 USP General Notices 2.30 Legal Recognition
`13 See § 201.57(c)(4); Labeling Review Tool (March 2022, page 29)
`
`Reference ID: 5458594
`
`13
`
`

`

`Assessor’s Comments
`(If an item is Inadequate, provide more details
`on the issues, as appropriate)
`
`The various dosage forms are
`described in adequate detailed and
`easily differentiated.
`Dosage form strengths are stated in
`metric units.
`Not a salt.
`
`Adequate
`
`Identifying characteristics are
`described in adequate detailed.
`
`N/A
`
`Not a tablet.
`
`N/A
`
`Not a parenteral product.
`
`Item
`
`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`DOSAGE FORMS AND STRENGTHS section
`Available dosage form(s)
`Adequate
`
`Strength(s) in metric system
`
`Adequate
`
`N/A
`
`If the active ingredient is a salt,
`apply the USP Salt Policy per
`FDA Guidance. Clearly state
`whether the strength is based on
`the active moiety (e.g., Tablets:
`10 mg of drug-x) or active
`ingredient (e.g., Tablets: 10 mg
`of drug-x hydrochloride). No
`equivalency statement.
`A description of the identifying
`characteristics of the dosage
`forms, including shape, color,
`coating, scoring, imprinting, and
`color and clarity of the solution,
`when applicable.
`Assess if the tablet is scored. If
`product meets guidelines and
`criteria for a scored tablet, state
`“functionally scored.”
`For injectable drug products for
`parenteral administration, use
`appropriate package type term
`(e.g., single-dose, multiple-dose,
`single-patient-use). Other
`package type terms include
`pharmacy bulk package and
`imaging bulk package (see USP
`<659>).
`
`Assessment: Adequate
`
`Section 3 is adequate.
`
`Reference ID: 5458594
`
`14
`
`

`

`1.2.3 Section 11 (DESCRIPTION)14
`
`(b) (4)
`
`Item
`
`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`
`Assessor’s Comments
`(If an item is Inadequate, provide more details
`on the issues, as appropriate)
`
`Adequate
`
`Adequate
`
`The proprietary name, CRENESSITY®
`is adequate.
`Single dose taken orally. This is
`adequate.
`
`N/A
`
`Not a salt.
`
`DESCRIPTION section
`Proprietary and established
`name(s)15 [§ 201.57(c)(12)(i)(A)].
`Dosage form(s) and route(s) of
`administration [§
`201.57(c)(12)(i)(B)].
`If the active ingredient is a salt,
`apply the USP Salt Policy and
`include the equivalency
`statement per Salt Guidance and
`MAPP. For example:
`“TRADENAME contains 100 mg
`of drug-x (equivalent to 123.7 mg
`of drug-x hydrochloride)” [§
`201.57(c)(12)(i)(C)].
`
`14 See § 201.57(c)(12); Labeling Review Tool (March 2022, page 56)
`15 Use of “USP” descriptor is not required to be included next to the established name throughout Prescribing
`Information (PI) labeling. If an applicant wants to use the “USP” descriptor next to the established name in
`the PI, recommend limiting its use to the product quality sections of the Full Prescribing Information (FPI)
`(i.e., DOSAGE FORMS AND STRENGTHS, DESCRIPTION, HOW SUPPLIED/STORAGE AND
`HANDLING) (see page 3 of LRT).
`
`Reference ID: 5458594
`
`15
`
`

`

`Item
`
`List inactive ingredients (not
`required for oral use, except for
`colorant) by the USP/NF names
`in alphabetical order.16 Avoid
`brand names. [§
`201.57(c)(12)(i)(C)].
`For parenteral injectable dosage
`forms, include the name and
`quantities of all inactive
`ingredients. For ingredients
`added to adjust the pH or make
`isotonic, include the name and
`statement of effect. [§
`201.100(b)(5)(iii)].
`If alcohol is present, must
`provide the amount of alcohol in
`terms of percent volume of
`absolute alcohol at 60 °F.
`(15.56 °C) [§ 201.10(d)(2)].
`Sterility statement (if applicable)
`[§ 201.57(c)(12)(i)(D)].
`Pharmacological/Therapeutic
`class17 [§ 201.57(c)(12)(i)(E)].
`Chemical name18, structural
`formula, molecular weight [§
`201.57(c)(12)(i)(F)].
`If radioactive, statement of
`important nuclear characteristics
`[§ 201.57(c)(12)(i)(G)].
`
`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`Adequate
`
`Assessor’s Comments
`(If an item is Inadequate, provide more details
`on the issues, as appropriate)
`
`The inactive ingredients changed to
`alphabetical list.
`
`N/A
`
`Not a parenteral product.
`
`N/A
`
`No alcohol present.
`
`N/A
`
`Not a sterile product.
`
`Adequate
`
`Adequate
`
`N/A
`
`Crinecerfont: corticotropin-releasing
`factor 1 antagonist.
`Chemical name, structure and
`molecular weight are adequately
`described.
`Not a radioactive product.
`
`16 Per § 201.100(b)(5)(i) and (ii), flavoring and colorants may be designated as such without naming their
`components except for FD&C Yellow No 5 and FD&C Yellow No 6, which must be listed per § 201.20. Per §
`201.100(b)(5)(iii), trace amounts of harmless substances added solely for individual product identification
`need not be named. If an applicant wants to use the National Formulary (NF) descriptor next to excipients,
`recommend limiting its use to the product quality sections of the FPI (see page 3 of LRT). Do not list brand
`names, e.g., Opadry, Eudragit, Polistirex, etc.
`17 Listed before “indicated for” in INDICATIONS AND USAGE of Highlights section [§ 201.57(a)(6)]; can also
`search the term “FDA EPC Text Phrases” in FDA’s Labeling Resources for Human Prescription Drugs for
`the most recent EPC list.
`18 Chemical names do not need to be capitalized unless it appears at the beginning of a sentence (see
`Preferred IUPAC Names Provisional Recommendation, September 2004; Chapter 1, par. 16 Name writing,
`p.80-90).
`
`Reference ID: 5458594
`
`16
`
`

`

`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`Adequate
`
`Assessor’s Comments
`(If an item is Inadequate, provide more details
`on the issues, as appropriate)
`
`Chemical and physical properties are
`described in adequate detail.
`
`N/A
`
`Gluten statement is not necessary.
`
`Adequate
`
`No misleading or promotional
`statements.
`
`N/A
`
`No USP labeling requirement.
`
`Item
`
`Other important chemical or
`physical properties (such as pKa
`or pH) [201.57(c)(12)(ii)].
`For oral prescription drug
`products, include gluten
`statement19 (if applicable).
`Remove statements that may be
`misleading or promotional (e.g.,
`“synthesized and developed by
`Drug Company X,” “structurally
`unique molecular entity”).
`If there is a USP monograph for
`the drug product and it contains
`a labeling requirement, ensure
`the labeling requirement is
`fulfilled. Note the labeling
`requirement may be applicable
`to another section of the PI (e.g.,
`Section 2).
`
`Assessment: Adequate
`
`With the correction to the inactive ingredient list, section 11 is adequate.
`
`1.2.4 Section 16 (HOW SUPPLIED/STORAGE AND HANDLING)20
`
`(b) (4)
`
`19 Draft guidance: Gluten in Drug Products and Associated Labeling Recommendations (December 2017)
`20 See § 201.57(c)(17); Labeling Review Tool (March 2022, page 70). Consider including proprietary name
`and established name.
`
`Reference ID: 5458594
`
`17
`
`

`

`Assessor’s Comments
`(If an item is Inadequate, provide more details
`on the issues, as appropriate)
`
`Each dosage form is described in
`adequate detail.
`Strengths are stated in metric system.
`
`25 mg and 50 mg: 60 capsules/bottle
`100 mg: 30 capsules/bottle
`Dosage forms are distinct and
`described clearly.
`
`Not a tablet.
`
`Not a parenteral product.
`
`Adequate
`
`Adequate
`
`Adequate
`
`N/A
`
`N/A
`
`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`HOW SUPPLIED/STORAGE AND HANDLING section
`Available dosage form(s)
`Adequate
`[§ 201.57(c)(17)].
`Strength(s) in metric system. [§
`201.57(c)(17)(i)] If the active
`ingredient is a salt, apply the
`USP Salt Policy per FDA
`Guidance. Clearly state whether
`the strength is based on the
`active moiety. No equivalency
`statement.
`Available units (e.g., bottles of
`100 tablets) [§ 201.57(c)(17)(ii)].
`Identification of dosage forms
`(e.g., shape, color, coating,
`scoring, imprinting, and color and
`clarity of the solution, when
`applicable); Include NDC(s) [§
`201.57(c)(17)(iii)].
`Assess if the tablet is scored. If
`product meets guidelines and
`criteria for a scored tablet, state
`“functionally scored.”
`For injectable drug products for
`parenteral administration, use
`appropriate package type term
`(e.g., single-dose, multiple-dose,
`single-patient-use). Other
`package terms include pharmacy
`bulk package and imaging bulk
`package (see USP <659>).
`
`Item
`
`Reference ID: 5458594
`
`18
`
`

`

`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`N/A
`
`Assessor’s Comments
`(If an item is Inadequate, provide more details
`on the issues, as appropriate)
`
`No special handling instruction.
`
`Adequate
`
`Storage conditions are described per
`USP <659> and in line with drug
`product stability data.
`
`N/A
`
`Not applicable.
`
`Adequate
`
`Added to section 16.
`
`Item
`
`Special handling about the
`supplied product (e.g., protect
`from light, refrigerate). If there is
`a statement to “Dispense in
`original container,” provide
`reason why (e.g., to protect from
`light or moisture, to maintain
`stability, etc.). For hazardous
`drugs, state “DRUG X is a
`hazardous drug. Follow
`applicable special handling and
`disposal procedures.x” with x
`numerical citation to “OSHA
`Hazardous Drugs.” [§
`201.57(c)(17)(iv)]
`Storage conditions. Where
`applicable, use USP storage
`range rather than storage at a
`single temperature. (see USP
`<659>).
`Latex: If product does not
`contain latex and manufacturing
`of product and container did not
`include use of natural rubber
`latex or synthetic derivatives of
`natural rubber latex, state: “Not
`made with natural rubber latex.
`Avoid statements such as “latex-
`free.”21
`Include information about child-
`resistant packaging22 (if chosen
`by manufacturer).
`
`Assessment: Adequate
`
`21 Guidance: Recommendations for Labeling Medical Products to Inform Users that the Product or Product
`Container is not Made with Natural Rubber Latex (December 2014)
`22 Guidance: Child-Resistant Packaging Statements in Drug Product Labeling (August 2019)
`
`Reference ID: 5458594
`
`19
`
`

`

`1.2.5 Other Sections of Labeling
`
`There may be other sections of labeling that contain product-quality related information. For
`example, there are specific required/recommended warnings for certain inactive ingredients
`[e.g., aspartame, aluminum in large and small volume parenterals, sulfites, FD&C Yellow
`Number 5 (tartrazine), and benzyl alcohol]. Please notify the prescription drug review
`division if the product contains any of these inactive ingredients.
`
`Please include your comments about other sections of labeling if they contain product
`quality information.
`
`1.2.6 Manufacturing Information After Section 17 (for drug products)23
`
`Item
`
`Item in Proposed
`Labeling
`(choose “Adequate” or
`“Inadequate”)
`Manufacturing Information After Section 17
`Name and location of business
`Adequate
`(street address, city, state, and
`zip code) of the manufacturer,
`distributor, and/or packer.
`
`Assessor’s Comments
`(If an item is Inadequate, provide more details
`on the issues, as appropriate)
`
`Requested to be added by another
`reviewer.
`
`Assessment: Adequate
`
`2.0 PATIENT LABELING
`
`Assessment of Product Quality Related Aspects of Patient Labeling (e.g., Medication
`Guides, Instructions for Use, Patient Information):
`
`Item
`
`Established name24
`Special preparation instructions
`(if applicable).
`Storage and handling information
`(if applicable).
`
`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`Adequate
`N/A
`
`Assessor’s Comments about
`Labeling
`(If an item is Inadequate, provide more
`details on the issues, as appropriate)
`CRENESSITY® is an adequate name.
`No special preparation necessary.
`
`Adequate
`
`Store CRENESSITY capsules at room
`temperature between 15°C to 25°C
`(59°F to 77°F).
`
`23 § 201.1(h)(5) and 201.1(i); Labeling Review Tool (March 2022, page 74)
`24 Established name = [Drug] [Route of Administration] [Dosage Form]
`
`Reference ID: 5458594
`
`20
`
`

`

`Item in Proposed
`Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`N/A
`
`Assessor’s Comments about
`Labeling
`(If an item is Inadequate, provide more
`details on the issues, as appropriate)
`No desiccant.
`
`Adequate
`
`Active ingredient is present
`
`Adequate
`
`Not necessary for capsule formulation.
`
`Adequate
`
`Neurocrine Biosciences, Inc., San
`Diego, CA 92130, U.S.A.
`
`Item
`
`If the product contains a
`desiccant, ensure the desiccant
`has a warning (e.g., “Do not
`eat.”) and the size and shape of
`the desiccant differ from the
`dosage form.
`Active ingredient(s) (if
`applicable).
`Alphabetical listing of inactive
`ingredients (if applicable).
`Name and location of business
`(street address, city, state, and
`zip code) of manufacturer,
`distributor, and/or packer.
`
`
`Assessment: Adequate
`
`
`
`3.0 CONTAINER AND CARTON LABELING25
`
`
`3.1 Container Labels26
`
`(b) (4)
`
`
`
`25 Carton and Container Labeling Resources
`26 Per § 201.10(h)(2)(i)(1), if the drug container is too small to bear all labeling information required by section
`502(e)(1)(A)(ii) and (B) of the FD&C Act, the container label should bear: proprietary name, established
`name, lot number, the name of the manufacturer, packer, or distributor of the drug.
`
`Reference ID: 5458594
`
`21
`
`

`

`3.2 Carton Labeling
`
`(Copy/paste or refer to a representative example of a proposed carton labeling)
`
`Item
`
`Proprietary name and
`established name27, (font size
`and prominence)
`[§ 201.10(g)(2)].
`Strength(s) in metric system
`[§ 201.100(b)(4) &
`201.100(d)].28
`Route(s) of administration, not
`required for oral use
`[§ 201.100(b)(3)].
`If the active ingredient is a
`salt, include the equivalency
`statement per Salt Guidance
`and MAPP [§ 201.10(d)(1) &
`201.100(b)(4), USP <1121>].
`Net contents (e.g., tablet
`count, volume of liquid)
`[§ 201.51(a)].29
`“Rx only” displayed on the
`principal display
`[§ 201.100(b)(1)].
`NDC (requested, but not
`required for all labels or
`labeling) [§ 201.2 & 207.35].
`Lot number and expiration
`date [§ 201.18 & 201.17].
`Storage conditions. If
`applicable, include a space on
`
`Item in Proposed
`Carton Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`
`Adequate
`
`Is item in
`Container
`Labels same
`as that of
`Carton
`Labeling?
` Yes
`
`Assessor’s Comments
`about Container Labels
`and Carton Labeling
`(If an item is Inadequate or
`different, provide more details, as
`appropriate)
`
`Name is present.
`
`Adequate
`
`Yes
`
`Strength is in metric on all
`three labels.
`
`N/A
`
`N/A
`
` Yes
`
`Oral capsule product not
`required.
`
`Yes
`
`Not a salt
`
`Adequate
`
`Yes
`
`# of capsules stated.
`
`Adequate
`
`Yes
`
`“Rx only” is present.
`
`Adequate
`
`Yes
`
`Present
`
`Adequate
`
`Adequate
`
`Yes
`
` Yes
`
`Present and adequately
`sized.
`Storage conditions
`described properly.
`
`27 Established name = [Drug] [Route of Administration] [Dosage Form]
`28 Express as “ XX mg per tablet” or “XX mg per capsule” for strength of professional samples of solid oral
`dosage form with small net quantities per container (e.g., 5 or less) or blister pack/carton. See Guidance:
`Safety Considerations for Container Labels and Carton Labeling Design to Minimize Medication Errors (May
`2022)
`29 § 201.51(h): A drug shall be exempt from compliance with the net quantity declaration required by this
`section if it is an ointment labeled "sample", "physician's sample", or a substantially similar statement and
`the contents of the package do not exceed 8 grams.
`
`Reference ID: 5458594
`
`22
`
`

`

`Item
`
`the carton labeling for the
`user to write the beyond-use-
`date (BUD).
`For injectable drug products
`for parenteral administration,
`use appropriate package type
`term (e.g., single-dose,
`multiple-dose, single-patient-
`use). Other package terms
`include pharmacy bulk
`package and imaging bulk
`package, and these products
`require a “Not for direct
`infusion” statement. (See USP
`<659>).
`Name of all inactive
`ingredients, in alphabetical
`order [§ 201.10(a)] [except for
`oral drug per § 201.100(b)(5)
`or limited space per §
`201.10(i)(2)].
`For parenteral injectable
`dosage forms, include
`quantities of all inactive
`ingredients. For ingredients
`added to adjust the pH or
`make isotonic, include the
`name and statement of effect.
`[§ 201.100(b)(5)(iii)].
`If alcohol is present, must
`provide the amount of alcohol
`in terms of percent volume of
`absolute alcohol at 60 °F.
`(15.56 °C) [§ 201.10(d)(2)].
`Linear Bar code [§
`201.25(c)(2)].30
`
`Item in Proposed
`Carton Labeling
`(choose “Adequate”,
`“Inadequate”, or “N/A”)
`
`Is item in
`Container
`Labels same
`as that of
`Carton
`Labeling?
`
`Assessor’s Comments
`about Container Labels
`and Carton Labeling
`(If an item is Inadequate or
`different, provide more details, as
`appropriate)
`
`N/A
`
` Yes
`
`Not a parenteral product.
`
`N/A
`
` Yes
`
`Oral drug product
`
`N/A
`
`Yes
`
`Not a parenteral product.
`
`N/A
`
`