CENTER FOR DRUG EVALUATION AND RESEARCH APPLICATION NUMBER: 211939Orig1s000 PRODUCT QUALITY REVIEW(S) Memorandum DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH Date: September 19, 2019 From: Mark R. Seggel, Ph.D. Application Technical Lead Office of New Drug Products Branch V/DNDP II Through: Moo-Jhong Rhee, Ph.D. Chief, Branch V Office of New Drug Products Branch V/DNDP II To: OPQ IQA #1 for NDA 211939 BONSITY (teriparatide injection) Subject: Final Recommendation - APPROVAL Summary: The OPQ Integrated Quality Assessment (IQA) #1 dated September 11, 2019 concluded that this 505(b)(2) NDA was Not Ready for Approval in its present form per 21 CFR 314.125(b)(8). It was noted that labeling (prescribing information (PI), pen label, and carton label) negotiations had not been completed, and in its present form, the labeling did not comply with the requirements under 21 CFR 201. The NDA was otherwise complete and adequate from the OPQ perspective. Deficiencies noted in OPQ IQA #1 Chapter IV, Labeling, included use of an incorrect established name, and incorrect presentation of the dosage form, strength, and package type. From the ONDP CMC perspective the revised labeling submitted August 23, 2019 (sn 0031), September 10, 2019 (sn 0036), and September 13, 2019 (sn 0037) adequately addresses the previously identified labeling issues. Additional Comments: Per the Panorama ‘Submission Facility Status View,’ all manufacturing, packaging and testing facilities associated with this NDA remain “Compliant.” ###### Reference ID: 44945304503479 Recommendation: This NDA is now recommended for Approval from the OPQ perspective. Application Technical Lead Signature: Mark R. Seggel, Ph.D., CMC Lead (acting) {see digital signature page} Attachment: Addendum to Labeling Review #1 14 Pages Have Been Withheld As A Duplicate Copy Of The " Review #1 of NDA 211939 Quality Assessment - Labeling" dated September 16, 2019 Which Is Located In This Chemistry Review Section Of This NDA Approval Package Reference ID: 44945304503479 Signature Page 1 of 1 -------------------------------------------------------------------------------------------- This is a representation of an electronic record that was signed electronically. Following this are manifestations of any and all electronic signatures for this electronic record. -------------------------------------------------------------------------------------------- /s/ ------------------------------------------------------------ MARK R SEGGEL 09/19/2019 04:32:21 PM Reference ID: 44945304503479 MEMORANDUM DEPARTMENT OF HEALTH AND HUMAN SERVICES PUBLIC HEALTH SERVICE FOOD AND DRUG ADMINISTRATION CENTER FOR DRUG EVALUATION AND RESEARCH DATE: September 16, 2019 TO: Review #1 of NDA 211939 Quality Assessment - Labeling FROM: Jane Chang, Ph.D. Senior Reviewer, ONDP/DNDP II/OPQ THROUGH Moo-Jhong Rhee, Ph.D. Chief, Branch V DNDP II/ONDP/OPQ SUBJECT: Final Recommendation on Labeling/Labels SUMMARY The previous Quality Assessment – Labeling, Assessment Cycle #1 dated 22-Jul-2019, made a recommendation of not ready for approval of this NDA because of labeling deficiencies (see N211939 Labeling R1, Section III). These labeling issues have been satisfactorily resolved based on the revisions made in eCTD-0031 and eCTD-0036, eCTD-0037. RECOMMENDATION: This application is now recommended for Approval from the CMC labeling/label perspective. Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum Assessment Notes Labeling deficiencies from Quality Assessment were identified in Assessment Cycle #1 dated 07/22/2019 (see N211939 Labeling R1, Section III). Subsequently, the following amendments were submitted and assessed. List Submissions being reviewed: Document Reviewed (eCTD #) Date Received eCTD-0031 (SDN-31) 08/23/2019 eCTD-0036 (SDN-36) 09/10/2019 eCTD-0037 (SDN-37) 09/13/2019 For convenience, the labeling deficiencies from Assessment Cycle #1 dated 07/22/2019 are repeated in this assessment in bold, followed by the applicant’s response. 1.0 PRESCRIBING INFORMATION a) Highlight Section 1. In the title, replace the established name “teriparatide [ (b) (4) injection” with “teriparatide injection”. Per FD&C Act 502(e)(3), the title of the USP monograph, i.e. Teriparatide Injection, is the established name. Furthermore, the year of initial U.S. approval should be 1987 instead of 2019 since teriparatide was first approved in 1987 for Parathar. 2. In the Dosage Forms and Strengths section, replace “ (b) (4) with “Injection: 620 mcg/2.48 mL (250 mcg/mL) in single-patient­ use pens”. b) Full Prescribing Information #3: Dosage Forms and Strengths 3. Add “Injection: 620 mcg/2.48 mL (250 mcg/mL)” at the beginning. Replace “ (b) (4) with “Single-patient-use pen”. #11: Description 4. Replace the established name “teriparatide [ (b) (4) injection” with “teriparatide injection”. 5. Include the molecular formula of teriparatide. That is, replace the second paragraph with the following: “The molecular formula of teriparatide is C181H291N55O51S2 and the molecular weight is 4117.8 daltons. Its amino acid sequence is shown below:” (b) (4) 6. Include the package type “single-patient-use”. Delete “ and “ (b) (4) Page 2 of 13 Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum (b) (4) 7. Replace “ with (b) (4) “as a free base (b) (4) 8. #16: How Supplied/Storage and Handling 9. In section 16.1: a. Replace “ (b) (4) with “BONSITY is available as single-patient-use pens in the following package size” b. Replace “ (b) (4) with “620 mcg/2.48 mL (250 mcg/mL)”. Provide the actual NDC number. In eCTD-0037, the Prescribing Information provided is shown below. 1.0 PRESCRIBING INFORMATION 1.1 HIGHLIGHTS OF PRESCRIBING INFORMATION 1) Title BONSITY (teriparatide injection), for subcutaneous use Initial U.S. Approval: 1987 2) DOSAGE FORMS AND STRENGTHS Injection: 620 mcg/2.48 mL (250 mcg/mL) in single-patient-use pen containing 28 daily doses of 20 mcg Page 3 of 13 Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum Assessor’s Comments and Item Information Provided in NDA Recommendations Drug name [201.57(a)(2)] Proprietary name and established name BONSITY (teriparatide injection) Acceptable The title of USP monograph, i.e. “teriparatide injection”, is the established name. Dosage form, route of administration Injection, subcutaneous Acceptable Controlled drug substance symbol (if N/A N/A applicable) Initial U.S. Approval 1987 Acceptable In 1987, FDA approved Parathar (discontinued in 1999) for teriparatide as NME. “Initial U.S. Approval” should be placed under proprietary name and established name, i.e. starting with a new line. However, this is a minor format issue. Dosage Forms and Strengths [201.57(a)(8)] Dosage Forms and Strengths Dosage form: Injection Acceptable Strength: 620 mcg/2.48 mL (250 mcg/mL) Whether the drug product is scored N/A N/A Package type single-patient-use Acceptable The package type “single-patient­ use” is included per FDA 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. 1.2 FULL PRESCRIBING INFORMATION 1.2.1 Section 3: DOSAGE FORMS AND STRENGTHS Injection: 620 mcg/2.48 mL (250 mcg/mL) Colorless solution in a single-patient-use pen containing 28 daily doses of 20 mcg. Page 4 of 13 Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum Assessor’s Comments and Item Information Provided in NDA Recommendations Available dosage forms injection Acceptable Active moiety expression of strength The strength of 620 mcg/2.48 mL Acceptable (b) (4) with equivalence statement (if (250 mcg/mL) and the dosage 20 applicable) mcg are expressed based on active moiety, i.e. free base. A description of the identifying Colorless solution Acceptable characteristics of the dosage forms, including shape, color, coating, scoring, and imprinting, when applicable. Package type single-patient-use Acceptable 1.2.2 Section 11: DESCRIPTION BONSITY (teriparatide injection) is a recombinant human parathyroid hormone analog (PTH 1-34). It has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone. The molecular formula of teriparatide is C181H291N55O51S2 and the molecular weight is 4117.8 daltons. Its amino acid sequence is shown below: Teriparatide is manufactured using a strain of Pseudomonas fluorescens modified by recombinant DNA technology. BONSITY is supplied as a sterile, colorless, clear, isotonic solution in a glass cartridge which is pre-assembled into a single-patient-use delivery device (pen) for subcutaneous injection. Each pen is filled to deliver 2.48 mL. Each mL contains 250 mcg teriparatide (as a free base), 0.41 mg glacial acetic acid, 0.10 mg sodium acetate, 45.4 mg mannitol, 3 mg metacresol, and water for injection. The drug product is a pH 4.0 solution. Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days. Page 5 of 13 Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum Assessor’s Comments and Item Information Provided in NDA Recommendations Proprietary name and BONSITY (teriparatide injection) Acceptable established name Dosage form and route of injection, subcutaneous