Product Quality Review(S)

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:” 6. Include the package type “single-patient-use”. Delete “ (b) (4) and “ (b) (4)

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Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum

7. Replace “ (b) (4) with “as a free base (b) (4) (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

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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.

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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.

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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 Acceptable administration Active moiety expression of Strength (250 mcg/mL) is expressed based on Acceptable strength with equivalence active moiety (free base). statement (if applicable) Inactive ingredient information Each mL contains 0.41 mg glacial acetic acid, Acceptable [quantitative, if injectables 0.10 mg sodium acetate, 45.4 mg mannitol, 3 21CFR201.100(b)(5)(iii), listed mg metacresol, and water for injection. by USP/NF names (if any)] Statement of being sterile (if “sterile” is included Acceptable applicable) Pharmacological/ therapeutic parathyroid hormone analog Acceptable class Per FDA Established Pharmacologic Class (EPC) Text Phrase, “parathyroid hormone analog” is the EPC. “recombinant human” is the descriptor. Chemical name, structural Chemical name is not provided, but amino acid Acceptable formula, molecular weight sequence is provided. For a 34-amino acid peptide, the Molecular weight: 4117.8 daltons use of three-letter code to express Molecular formula: C181H291N55O51S2. the primary structure, in lieu of Structural formula is provided as the primary the chemical name or structural sequence using three-letter code for each amino formula, is acceptable. acid. If radioactive, statement of N/A N/A important nuclear characteristics. Other important chemical or pH 4.0 Acceptable physical properties (such as pKa or pH) Package type single-patient-use Acceptable

1.2.3 Section 16: HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied BONSITY is available as single-patient-use pens in the following package size:  620 mcg/2.48 mL (250 mcg/mL) NDC #####-652-89. 16.2 Storage and Handling

 The BONSITY delivery device should be stored under refrigeration at 2°C to 8°C (36°F to 46°F) at all times.  Recap the delivery device when not in use to protect the cartridge from physical damage and light.  During the use period, time out of the refrigerator should be minimized; the dose may be delivered immediately following removal from the refrigerator.

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Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum

 Do not freeze. Do not use BONSITY if it has been frozen.

Assessor’s Comments and Item Information Provided in NDA Recommendations Strength of dosage form 620 mcg/2.48 mL (250 mcg/mL) Acceptable Available units (e.g., bottles 2.48 mL as single-patient-use pens Acceptable of 100 tablets) See above for strength information. Identification of dosage NDC #####-652-89 Acceptable forms, e.g., shape, color, Pfenex stated that they have initiated coating, scoring, imprinting, the registration process for the NDC number company’s code (the first segment of the NDC number), which is assigned by FDA. Special handling (e.g., protect Do not freeze. Recap the delivery device Acceptable from light) when not in use. Storage conditions stored under refrigeration at 2°C to 8°C (36°F Acceptable to 46°F) Package Type single-patient-use Acceptable

1.2.4 Section 17: PATIENT COUNSELING INFORMATION

Assessor’s Comments and Item Information Provided in NDA Recommendations Manufacturer/distributor Marketed by: Pfenex, Inc. Acceptable name [21 CFR 201.1(h)(5)] San Diego, CA 92121, USA

Assessment: Adequate Section 11 Description (b) (4)

(b) (4) it is acceptable that only the structural formula of the active moiety (free base) is displayed. The strength of the drug product is based on teriparatide free base. In the Labeling Assessment Cycle #1 dated 07/22/2019, a descriptor “as a free base (b) (4) was recommended for strength. (b) (4)

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Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum

(b) (4) the descriptor “ (b) (4) is not necessary. Therefore, only “as a free base” is included.

The pH of the drug product solution, pH 4.0, is controlled via (b) (4) (b) (4)

Overall The labeling issues identified in Assessment Cycle #1 dated 07/22/2019 have been addressed. Labeling information pertaining to CMC in Prescribing Information meets the regulatory requirements.

2.0 PATIENT LABELING 2.1 MEDICATION GUIDE Information provided in eCTD-0037 is summarized below.

Assessor’s Comments and Item Information Provided in NDA Recommendations Proprietary name and BONSITY (teriparatide injection) Acceptable established name Manufacturer/distributor name Marketed by: Pfenex, Inc. Acceptable [21 CFR 201.1(h)(5)] San Diego, CA 92121, USA

2.1 USER MANUAL Information provided in eCTD-0036 is summarized below.

Assessor’s Comments and Item Information Provided in NDA Recommendations Proprietary name and BONSITY (teriparatide injection) Acceptable established name Package Type single-patient-use Acceptable

Assessment: Adequate Labeling information pertaining to CMC in the Medication Guide and User Manual meets the regulatory requirements.

3.0 CARTON AND CONTAINER LABELS The following issues were identified in Assessment Cycle #1 dated 07/22/2019.

1. Address the following for both container and carton labels: a Replace the established name “teriparatide [ (b) (4) injection” with “teriparatide injection”. Per FD&C Act

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Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum

502(e)(3), the title of the USP monograph, i.e. Teriparatide Injection, is the established name b Place the strength “620 mcg/2.48 mL (250 mcg/mL)” directly underneath the established name c The “Rx only” statement should be displayed prominently d Replace “ (b) (4) (b) (4) ” with “Each single-patient-use pen will deliver 28 subcutaneous doses” 2. Address the following to the container label: a Add a statement “Rx only” b Add Bar code c Add NDC number if space is permitted 3. Address the following to the carton label: (b) (4) a

b Add “See package insert for dosage information”. c Indicate the locations of Lot number and expiration date. d Provide the actual NDC number e Delete the statement “ (b) (4) (b) (4) ”

Assessor’s Comments: In the FDA Information Request Letter dated 08/19/2019, only Items 1a, 1b, 1d, 2a, 2b, 2c, 3c, 3d, and 3e as identified in the Assessment Cycle #1 dated 07/22/2019 were conveyed to the applicant. That is, Items 1c and 3a were not included. Item 3b for the carton label was replaced with “Recommended Dosage: See Prescribing Information”. Regarding Item 3b, DMEPA assessor, Ebony Whaley, stated that based on DMEPA management’s involvement with the Labeling Workgroup, it was recently determined that the usual dosage statement “Recommended Dosage: See Prescribing Information” be used instead of “See package insert for dosage information”. Item 1c was not conveyed because the “Rx only” statement is not required to be prominent. In addition, DMEPA assessor, Ebony Whaley, recommended reducing the prominence of the Rx only statement on the carton label (see the IR Letter dated 08/19/2019).

(b) (4), (b) (5)

Therefore, Item 3a was not included in the FDA IR dated 08/19/2019.

3.1 CONTAINER LABEL In eCTD-0031, the container label provided is shown below.

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Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum

(b) (4)

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Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum

Assessor’s Comments and Item Information Provided in NDA Recommendations Proprietary name, established BONSITY Acceptable name [font size and prominence, teriparatide injection “[ (b) (4) has been deleted 21 CFR 201.10(g)(2)] from the established name. The font size of established name is greater than 50% of the proprietary name. Route of administration, if it is subcutaneous Acceptable not for oral use Active moiety expression of 620 mcg/2.48 mL (250 mcg/mL) Acceptable strength with equivalence (b) (4) statement (if applicable) [FD&C Act 502(e)(1)(ii), 21 CFR 201.10(d)(1); 21 CFR 201.100(b)(4), USP <1121>] Net content [21 CFR 201.51(a)] 620 mcg/2.48 mL Acceptable Name of all inactive ingredients Not provided. Acceptable per 201.10(a) [except for oral Due to limited space, it is acceptable drug per 201.100(b)(5) or limited that inactive ingredients are not listed space per 201.10(i)(2)] per 201.10(i)(2). “Rx only” displayed on the main Provided under NDC number. Acceptable panel NDC number [21 CFR 201.2 or XXXXX-652-89 Acceptable 21 CFR 207.35(b)(3)(i)] Per 21 CFR 207.33(b)(i), the first segment of the NDC code represents the labeler code and is assigned by FDA. The actual value of this 5-digit code is not provided, still pending assignment by FDA. Lot number (21 CFR 201.18) and The location of Lot number and expiration Acceptable expiration date (21 CFR 201.17) date are allocated. Storage conditions REFRIGERATE – DO NOT FREEZE Acceptable Even though no numerical temperature is provided, it is considered acceptable due to space limitation. Numerical temperature range is provided in the carton label. Bar code (21CFR 201.25) The location of Bar code is indicated Acceptable Name of manufacturer/distributor Marketed by: Pfenex, Inc. Acceptable San Diego, CA 92121, USA Others, if space is available Throw away 28 days after first use. Acceptable Do NOT transfer contents to a syringe. Read User manual BEFORE Injection. Package type single-patient-use Acceptable

Assessment: Adequate The issues identified for container label in Assessment Cycle #1 dated 07/22/2019 have been addressed. Regarding the expression of strength, per USP <7>, for injectable drug products greater than 1 mL, the quantity per total volume should be the primary and prominent expression on the principal display panel of the label, followed in close proximity by

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Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum

quantity per milliliter enclosed by parentheses (quantity/mL). The total volume of this (b) (4) NDA drug product is the volume corresponding to doses, i.e. 2.48 mL, instead of the withdrawable volume (i.e. NL (b) (4) mL, see N211939-DP R01, page 9) in the drug (b) (4) product cartridge. This is because the injector pen is designed such that onl doses can be delivered. The pen includes an active stop which prevents the setting of any additional dose after delivery of the (b) (4)dose (see N211939-DP R01, page 29).

3.2 CARTON LABEL In eCTD-0031, the carton label provided is shown below. (b) (4)

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Reference ID: 4503479 NDA 211939 Quality Assessment - Labeling Assessment Cycle #1 Addendum

Assessor’s Comments and Item Information Provided in NDA Recommendations Proprietary name, established BONSITY Acceptable name [font size and prominence, teriparatide injection “[ (b) (4) has been deleted 21 CFR 201.10(g)(2)] from the established name. The font size of established name is greater than 50% of the proprietary name. Route of Administration subcutaneous Acceptable Dosage strength 620 mcg/2.48 mL (250 mcg/mL) Acceptable Net contents [21 CFR 201.51(a)] 1 prefilled pen Acceptable Name of all inactive ingredients. Each mL contains 0.41 mg glacial acetic Acceptable Quantitative ingredient acid, 0.10 mg sodium acetate, 45.4 mg Quantitative amounts for all information is required for mannitol, 3 mg metacresol, and water for excipients are provided. injectables. injection “Rx only” displayed on the main “Rx only” is provided. Acceptable panel Statement of being sterile (if “Sterile” is provided Acceptable applicable) NDC number [21 CFR NDC number (XXXXX-652-89) is Acceptable 207.35(b)(3)(i)] provided. Per 21 CFR 207.33(b)(i), the first segment of the NDC code represents the labeler code and is assigned by FDA. The actual value of this 5-digit code is not provided, still pending assignment by FDA. Lot number (21 CFR 201.18) and Locations are allocated. Acceptable expiration date (21 CFR 201.17) Storage conditions Keep in refrigerator at 2° to 8° (36° to Acceptable 46°F). Do NOT freeze. Bar code (21CFR 201.25) Bar Code is allocated. Acceptable

“Recommended Dosage: See Provided. Acceptable Prescribing Information” “Keep out of reach of children” Not provided. Acceptable (Required for OTC in CFR. Optional for Rx drugs) Name of manufacturer/distributor Marketed by: Pfenex, Inc. Acceptable San Diego, CA 92121, USA Others, if space is available Preset dose: 20 mcg teriparatide once daily. Acceptable Do NOT transfer contents to a syringe. Not a child-resistant container. Needles not included. Becton, Dickinson and Company pen needles from 29 to 31 gauge are recommended for use with this device. Package type single-patient-use Acceptable

Reviewer’s Assessment: Adequate The issues identified for carton label in Assessment Cycle #1 dated 07/22/2019 have been addressed.

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Reference ID: 4503479 Jane Digitally signed by Jane Chang Chang Date: 9/16/2019 01:17:10PM GUID: 5034f819000053b21e2574590781f330

Moo Jhong Digitally signed by Moo Jhong Rhee Rhee Date: 9/16/2019 01:19:32PM GUID: 502d0913000029f9798ca689a802fa55

Reference ID: 4503479 QUALITY ASSESSMENT

Recommendation: As of this review, this 505(b)(2) NDA is Not Ready for Approval in its present form per 21 CFR 314.125(b)(8).

NDA 211939 Review # 1

BONSITY (teriparatide injection)

Drug Name/Dosage Form Teriparatide Injection Strength 20 mcg / 80 L in a multi-dose pen injector Route of Administration subcutaneous injection Rx/OTC Dispensed Rx Applicant Pfenex, Inc. US agent, if applicable -

SUBMISSION(S) DOCUMENT DISCIPLINE(S) AFFECTED REVIEWED DATE Original (0001) 12/07/18 Multi-discipline Amendment (0004) 02/12/19 CDRH; Process/Facilities Amendment (0010) 04/01/19 CDRH Amendment (0011) 04/03/19 Product Quality Microbiology Amendment (0016) 05/03/19 Product Quality Microbiology Amendment (0018) 05/22/19 Drug Product Amendment (0019) 05/22/19 Product Quality Microbiology Amendment (0020) 05/29/19 Drug Substance Amendment (0021) 06/03/19 CDRH Amendment (0022) 06/17/19 Drug Substance; Drug Product Amendment (0023) 06/17/19 CDRH Amendment (0024) 06/25/19 CDRH Amendment (0025) 06/26/19 Product Quality Microbiology Amendment (0027) 07/09/19 Drug Substance Amendment (0028) 07/15/19 CDRH Amendment (0029) 08/08/19 CDRH Amendment (0031) 08/23/19 Labeling Amendment (0034) 08/29/19 CDRH Amendment (0035) 09/03/19 CDRH

Reference ID: 44902224503479 QUALITY ASSESSMENT

Quality Review Team DISCIPLINE REVIEWER BRANCH/DIVISION Drug Substance Larry Perez NDBII / DNDAPI /ONDP Drug Product / Labeling / EA Jane Chang NDPBV / DNDPII / ONDP Process / Facilities Jingbo Xiao PABV / DPAII / OPF Microbiology Maritere Carattini MABIII / DMA / OPF RBPM Grafton Adams RBPMBI / DRBPMI / OPRO Application Technical Lead Mark Seggel NDPBV / DNDPII / ONDP

Reference ID: 44902224503479 QUALITY ASSESSMENT

Quality Review Data Sheet

1. RELATED/SUPPORTING DOCUMENTS

A. DMFs: Date Review DMF # Type Holder Item Referenced Status Comments (b) (4) Completed (b) (4) III Adequate Micro. review 04/10/19 CMC review 03/29/19 III N/A See IQA Chapter II, Drug Product V Adequate Micro. review 05/08/19

III Adequate 09/06/11 See IQA Chapter (see DMF (b) (4) II, Drug Product N/A: There is enough data in the application, therefore the DMF did not need to be reviewed.

B. Other Documents: IND, RLD, or sister applications DOCUMENT APPLICATION NUMBER DESCRIPTION IND submissions, associated IND 129196 Pfenex, Inc. IND for PF708 reviews and meeting minutes (teriparatide injection)

2. CONSULTS

DISCIPLINE STATUS RECOMMENDATION DATE REVIEWER Biostatistics na Pharmacology/ na Toxicology CDRH Completed Approvable from device 09/04/19 M. Ondeck engineering and GMP perspectives Clinical na na: not applicable

Reference ID: 44902224503479 QUALITY ASSESSMENT

Executive Summary

I. Recommendations and Conclusion on Approvability

In its present form, Pfenex, Inc.’s 505(b)(2) New Drug Application #211939, for Bonsity (teriparatide injection), 20 g per 80 L subcutaneous injection, is not ready for approval. Labeling (package insert, container/carton) negotiations have not been completed, and in its present form, the labeling does not comply with the requirements under 21 CFR 201.

Bonsity (teriparatide injection) is a drug-device combination product.

Sufficient information and supporting data have been provided in accordance with 21 CFR 314.50 to ensure the identity, strength, quality, purity, and potency of the drug product component (a sterile, aqueous solution of teriparatide in a glass cartridge).

The device component consists of an (b) (4)disposable, fixed-dose, multi- dose, single-patient use pen injector. CDRH has determined that the device constituent parts of the combination product are approvable. Adequate documentation of compliance with the applicable sections of the medical device Quality System Regulations under 21 CFR 820 has been provided. The application therefore complies with the requirements for a drug-device combination product under 21 CFR Part 4.

The drug substance, drug product, and drug-device combination product manufacturing, packaging and testing facilities have acceptable GMP status.

The claimed categorical exemption from the environmental assessment requirements in accordance with 21 CFR 25.31(b) is acceptable.

POSTMARKETING COMMITMENTS

Not applicable.

II. Summary of Quality Assessments

A. Product Overview

Proposed Indication(s) including • Treatment of postmenopausal women with Intended Patient Population osteoporosis at high risk for fracture • Increase of bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture • Treatment of men and women with osteoporosis associated with sustained systemic glucocorticoid therapy at high risk for fracture Duration of Treatment Use for longer than 2 years during a patient’s lifetime is not recommended.

Reference ID: 44902224503479 QUALITY ASSESSMENT

Maximum Daily Dose 20 mcg subcutaneously once a day Alternative Methods of Not applicable Administration

Teriparatide is a human parathyroid hormone analog (1-34), [PTH(1-34)] for treatment of osteoporosis. It has an identical sequence to the 34 N-terminal amino acids (the biologically active region) of the 84-amino acid human parathyroid hormone.

Pfenex’s Bonsity (teriparatide injection) is a drug-device combination product designed to be therapeutically equivalent to E. Lilly’s Forteo (teriparatide injection; NDA 21318, approved November 26, 2002). Because it manufactured using recombinant technology, Bonsity is subject to review as a 505(b)(2) application rather than as a 505(j) generic. Note that the first teriparatide-containing drug product, Parathar, was approved in 1987.

While Bonsity is intended to be therapeutically equivalent to Forteo, the two differ in several ways. Bonsity and Forteo differ in the manufacture of the drug substances. Forteo teriparatide is manufactured by (b) (4) using a strain of Escherichia coli modified by recombinant DNA technology while Bonsity teriparatide is manufactured using a strain of Pseudomonas fluorescens modified by recombinant DNA technology.

Although the pen injectors (i.e., the device components) of Forteo (b) (4) and Bonsity are not identical, the overall performance of each is similar. Both devices are designed to deliver a 20 mcg (80 µL) dose subcutaneously by depressing the actuation button on the pens. Each multi-dose, single patient pen contains sufficient drug product to deliver 28 doses. (b) (4)

Each milliliter of Bonsity contains 250 mcg teriparatide ( (b) (4) 0.41 mg glacial acetic acid, 0.10 mg sodium acetate, 45.4 mg mannitol, 3 mg metacresol, and water for injection. The formulation is virtually identical to that of Forteo. (b) (4) (b) (4)

As a 505(b)(2) application referencing E. Lilly’s NDA 21318 for Forteo, establishment of a ‘quality bridge’ between Bonsity and Forteo was necessary. The results of a wide range of analytical techniques applied to Forteo, Bonsity and the Teriparatide USP reference standard demonstrate the same primary structure of teriparatide drug substance in both drug products and a high degree of similarity in terms of purity, physiochemical, secondary and tertiary structures, and functional properties.

USP monographs have been established for both teriparatide and teriparatide injection. Bonsity meets the USP monograph requirements for teriparatide injection.

Reference ID: 44902224503479 QUALITY ASSESSMENT

The OPQ/OBP product quality/immunogenicity review team determined that the assays for characterizing the clinical immunogenicity of Bonsity were adequately validated. No significant differences in immunogenicity of Bonsity and Forteo were observed. Results of a relative bioavailability study confirmed that Bonsity is bioequivalent to Forteo. Bonsity (teriparatide injection) should therefore provide a safe and efficacious alternative to Forteo with no differences in overall benefit / risk.

B. Quality Assessment Overview

Drug Substance: Teriparatide drug substance (referred to as PF708 by Pfenex) is manufactured by (b) (4) with a rDNA-modified strain of Pseudomonas fluorescens (b) (4)

(b) (4)

(b) (4) . The overall control strategy for the critical steps and intermediates for the has been sufficiently described and is acceptable for manufacturing of teriparatide drug substance.

Bonsity teriparatide (PF708) has been extensively characterized by chemical, physical, spectroscopic, and chromatographic methods. The primary structure of Bonsity teriparatide has been confirmed. Multiple comparative analyses, including the determination of secondary structure, higher-order structures, absolute and relative mass, size, and purity, indicate that PF708 is highly similar to Forteo teriparatide. The host cell protein and endotoxin levels in PF708 were well below the regulatory limits.

PF708 complies with the current USP monograph tests for identification, bioidentity, endotoxins and, with the exception of the limit for total oxidation impurities (Met8, Met18, and Met8,18), product-related impurities. While the limit for total oxidation impurities of not more than (NMT) (b) (4)% in PF708 (b) (4) the USP limit of NMT 0.5%, the limits for related impurities in the drug product comply with the USP monograph for teriparatide

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injection. Impurities with molecular masses greater than teriparatide (i.e., aggregates including dimers, etc.) are limited to NMT (b) (4)%.

(b) (4) (b) (4) A month retest period has been established for drug substance stored at C

Overall, the information on the drug substance supports APPROVAL of the NDA from the drug substance review team perspective (see IQA Chapter I for details).

Drug Product: The drug product consists of a sterile solution in a glass cartridge fitted (b) (4) with a rubber septum and rubber plunger. The cartridge is filled with approximately mL of teriparatide injection which is sufficient to provide 28 injections of 80 µL. Each milliliter contains 250 mcg teriparatide, 0.41 mg glacial acetic acid, 0.10 mg sodium acetate, 45.4 mg mannitol, 3 mg metacresol, and water for injection. (b) (4)

pH 4 (b) (4) The filled cartridge is assembled into a (b) (4) multi-dose, single-patient use, pen injector.

Three Bonsity drug product cartridge lots were compared with three Forteo drug product lots with respect to pH, impurity profiles (by RP-HPLC, CEX-HPLC, SE-HPLC, and SDS-PAGE), primary structure (by Intact mass and peptide mapping), secondary structure (by Far-UV Circular Dichroism), tertiary structure (by Intrinsic Fluorescence), and functional properties (by Biolayer Interferometry Receptor-Binding Assay and cAMP bioassay). The results support the same primary structure of teriparatide drug substance in both drug products and a high degree of similarity in terms of purity, physiochemical, secondary and tertiary structures, and functional properties

Drug product (filled cartridge) specification includes tests for visual inspection, pH, particulate matter by light obscuration, sterility, bacterial endotoxins, identification and assay (teriparatide) by RP-HPLC, metacresol content by GC, product-related impurities (specified, each unspecified, and total impurities) by RP- HPLC, aggregates by SE-HPLC (b) (4) (nmt %, as revised), bioidentity, and container content for injections (not less than (b) (4) mL). The product specification includes essential performance requirements (i.e., break loose force and sustaining glide force). The suitability of the analytical procedures has been adequately demonstrated.

The finished drug-device combination product specification includes tests for identification of teriparatide, visual inspection, functional operation, and essential (b) (4) performance requirements (dose accuracy [80 µL µL], injection force and dose button pull force).

A 24-month expiration dating period when stored at long-term storage at 2ºC-8ºC is supported by the available stability data. (b) (4) .

Overall, the application is recommended for APPROVAL from the drug product review perspective (see IQA Chapter II for details). Refer to the September 4, 2019 CDRH

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review for details of essential performance requirements testing of the finished drug- device combination product.

Environmental Analysis: Pfenex requested a categorical exclusion of the requirements of an environmental impact assessment under 21 CFR 25.31(b) for teriparatide injection, on the basis that the estimated concentrations of the drug substance at the point of entry into the aquatic environment will be below 1 part per billion. Furthermore, the applicant knows of no extraordinary circumstances that might cause a significant effect on the quality of the human environment. The claimed categorical exclusion is acceptable (see IQA Chapter II).

Labeling: As of this review, labeling (PI, pen injector label, carton) negotiations have not been completed and its present form the labeling is inadequate. From the ONDP perspective, this application is therefore NOT READY FOR APPROVAL. Recommended revisions to the labeling include deletion of ‘[ (b) (4) from the established name (to conform with the USP monograph title), presentation of the strength as “620 mcg/2.48 mL (250 mcg/mL), and description of the package type as “single patient-use” per FDA guidance. See IQA Chapter IV for additional comments. An addendum to this IQA will be completed upon submission of revised labeling.

Process: The drug product manufacturing process involves the following steps: (b) (4)

NDA 211939, as amended, is recommended for APPROVAL from the process review perspective.

Facilities: The drug substance, drug product, and drug-device combination product manufacturing, packaging and testing facilities have acceptable GMP status. An overall manufacturing inspection recommendation of APPROVE was issued on July 30, 2019. See IQA Chapter VI and the CDRH review for additional details.

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Biopharmaceutics: Not applicable to this application for a sterile aqueous solution for subcutaneous injection.

Microbiology : The drug product is sterilized by (b) (4) . The sterile, aqueous solution of teriparatide includes (b) (4) a preservative, (b) (4) .

(b) (4)

Adequate controls have been established. Completed process validation studies demonstrate the overall suitability of the manufacturing process with respect to product sterility.

Antimicrobial effectiveness testing (AET) demonstrated the adequacy of the preservative throughout the shelf-life (24 months) and in-use period (28 days) of the product.

The applicant’s verification of container closure integrity is consistent with regulatory expectations for a sterile pharmaceutical product. The drug product specification includes tests for sterility and endotoxins.

From the product quality microbiology perspective this application is ADEQUATE (see IQA Chapter VII).

Device: The device component of Bonsity is a manually operated “pull and push” type, fixed-dose, multiple-dose, single-patient use, disposable pen injector. It is an ISO 11608 system designation C pen injector. The device constituent parts (subassemblies) are manufactured at (b) (4) PF708 drug product cartridges, as well as both subassemblies, are shipped to (b) (4) for PF708 drug product pen injector assembly.

The PF708 drug product pen injector is designed to administer the doses from an integrated, non-replaceable 3-mL cartridge pre-filled with drug product using commercially available pen needles (e.g., BD 29-31 G ultrafine pen needles). The PF708 (b) pen injector contains (4) full doses. An active stop in the PF708 pen injector prevents the (b) setting of any additional dose after delivery of the (4) st dose. The patient is instructed to use a dose daily for 28 days. The entire pen injector is to be disposed 28 days after first use. The dose is preset to 80 µL.

Two clinical trials, PF708-101 and PF708-301, were completed using the PF708 drug product pen injector. Since the completion of the clinical program, minor modifications were made to the pen injector. However, no changes were made to the materials, user interface, or principle of operation of the device. The design intent (specifically design input requirements) and design output specifications and performance remain the same, as confirmed by design verification testing.

(b) (4) at CDRH request device performance is

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controlled at two stages, i.e., testing of the filled cartridge and testing of the assembled pen injector. The filled cartridge specification is discussed in the section on the Drug Product (IQA Chapter II). The finished drug-device combination product specification (b) (b) now includes tests for injection force (nmt (4)N) and dose button pull force (nlt (4) N and (b) (4) nmt N). Note that the acceptance criterion for injection force of the final finished combination product is relatively low, even for users with osteoporosis.

Data has been provided adequately demonstrating that the product will meet essential performance requirements through the 24-month shelf-life.

The applicant has leveraged data available on product sent from the assembly site in (b) (4) to demonstrate that conditions like to be experienced during normal transit (e.g., shock, vibration stacking, pressure) do not adversely impact product performance. A formal shipping verification study (to confirm that the device will function to specification after shipping) will be completed prior to commercial distribution of the product.

Pfenex has a drug-based streamlined approach for compliance to 21 CFR 4.4 (b)(1), their design control procedures for the development of combination products with a device constituent are developed per 21 CFR 820.30. This specific pen injector device was developed in conjunction with a contractor, (b) (4) maintains the DHF for each batch of pen injector subassembly components and the DMR for the design of the subassembly components, and Pfenex maintains the DHF for the combination product.

CDRH has determined that the device constituent parts of the combination product are APPROVABLE. Adequate documentation of compliance with the applicable sections of the medical device Quality System Regulations under 21 CFR 820 has been provided. The application therefore complies with the requirements for a drug-device combination product under 21 CFR Part 4. See the September 4, 2019 CDRH review for a detailed assessment of the device.

Analytical Methods Verification: Verification of the drug substance and drug product analytical methods by the CDER/OPQ/OTR St. Louis laboratory is not warranted. USP teriparatide and teriparatide monograph methods are followed for identification, bioidentity, assay, and related substances. Other tests are performed in accordance with USP general procedures. Tests for residual host cell proteins, residual DNA, peptide mapping, metacresol content, aggregates, and device function are straightforward and do not require OTR verification.

C. Special Product Quality Labeling Recommendations

Not Applicable

D. Final Risk Assessment (see Attachment I)

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OVERALL ASSESSMENT AND SIGNATURES:

Application Technical Lead Name: Mark R. Seggel, Ph.D. CMC Lead (acting)

{see electronic signature page}

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CHAPTERS: Primary Quality Assessment

CHAPTER I: Drug Substance CHAPTER II: Drug Product CHAPTER III: Environmental Assessment (See Chapter II) CHAPTER IV: Labeling CHAPTER V: Process CHAPTER VI: Facilities CHAPTER VII: Microbiology CHAPTER VIII: Biopharmaceutics (Not Applicable) CHAPTER IX: Additional Quality Discipline (Not Applicable) Attachment I: Risk Assessment / Life Cycle Management Attachment II: List of Deficiencies for Complete Response (Not Applicable) Attachment III: Product Specification

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ATTACHMENT I: Product Risk Assessments

Initial Risk Assessment for NDA 211939 Teriparatide Injection Product Attribute / Factors that can impact Probability Severity of Detectability FMECA Comment CQA the CQA (O) Effect (S) (D) RPN Number Appearance • Process 1 3 2 6 • Stability Assay (active) / • Formulation Long-term storage under refrigeration; Stability • Raw materials 1-month in use at room temperature • Process 4 2 3 24 90-105% • Container closure • Storage conditions Assay (metacresol) • Formulation 3 mg/mL ± (b) % • Raw materials 3 4 3 36 (4) • Process pH • Formulation Drug substance solution prepared at • Raw materials (b) (4) • Process 2 3 1 6

Related Substances • Formulation Teriparatide subject to hydrolysis and Impurities / • Raw materials oxidation, succinimide formation 4 3 3 36 Degradants • Process Photolabile. • Container/Closure (b) Aggregation • Formulation Limit: nmt (4) % • Raw materials 3 3 4 36 • Process • Storage Leachables / • Formulation Aqueous system. Potential L/E from Extractables • Raw materials 2 3 4 24 plunger and septum, glass (b) (4) • Container/Closure Uniformity of • Process parameters Cartridge min. fill (b) (4) Dosage Pen originally designed for (b) 2 2 2 8 Fill Volume (2.48 mL); Label: 28 doses(4) x 80 L (b) (4) Dose Accuracy • Container/Closure Multi-dose, fixed dose, disposable pen injection system delivering 80 L (20 2 3 3 18 g); pen injector subject to CDRH ODE device review Osmolality • Formulation Testing not proposed • Raw materials 1 1 1 1 • Process Foreign Particulate • Raw materials Per USP <788> Matter • Process 3 3 3 27 • Container closure Sterility • Raw materials Subcutaneously injected drug product. • Process parameters 4 4 5 80 Sterility assurance is critical! Sterile • Hold time (b) (4) . Endotoxins • Raw materials (b) (4) 2 4 4 32

Device Function • Materials CDRH to assess (pen injector) • Assembly process 3 3 3 27 • Storage RPN Values: Low Risk (1-25); Moderate Risk (26-60); High Risk (61-125)

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Final Risk Assessment From Initial Risk Identification Review Assessment Lifecycle Factors that can Initial Risk Risk Mitigation Attribute/ CQA Final Risk Evaluation Considerations/ impact the CQA Ranking* Approach Comments Appearance • Process Acceptable None. 6 • Stability Assay (active) / • Formulation Acceptable Proposed shelf-life (24 Stability • Raw materials months) granted. • Process 24 Extensions will need to be • Container closure supported with real-time • Storage conditions data. Assay (metacresol) • Formulation (b) (4) Acceptable • Raw materials 36 • Process

pH • Formulation Acceptable • Raw materials 6 • Process Related Substances • Formulation Acceptable Impurities / • Raw materials 36 Degradants • Process • Container/Closure (b) Aggregation • Formulation Acceptable Limit revised to nmt (4) % • Raw materials 36 • Process • Storage Leachables / • Formulation (b) (4) Acceptable Extractables • Raw materials 24 • Container/Closure Uniformity of Dosage • Process parameters Acceptable 8 Fill Volume Dose Accuracy • Container/Closure Acceptable Any proposed changes to 18 the pen injector should be carefully evaluated Osmolality • Formulation Acceptable Testing not proposed. • Raw materials 1 Small injection volume. • Process Foreign Particulate • Raw materials Acceptable Matter • Process 27 • Container closure

Sterility • Raw materials Acceptable Manufacturing changes • Process parameters that could affect the • Hold time microbiological quality of the subject drug product. 80

Endotoxins • Raw materials Acceptable

Device Function • Materials Acceptable (pen injector) • Assembly process 27 • Storage

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ATTACHMENT II: List of Deficiencies for Complete Response

Not Applicable.

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ATTACHMENT III: Product Specification

The product specification was updated on September 3, 2019 to include revisions requested by CDRH. It is included here as a replacement for the earlier version provided in IQA Chapter II, Drug Product.

Bonsity (teriparatide injection) Drug Product Cartridge

(b) (4)

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(b) (4)

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Bonsity (teriparatide injection) Finished Drug -Device Combination Product

(b) (4)

(b) (4) (b) (4)

(b) (4)

(b) (4) (b) (4)

Reference ID: 4490222 4503479 Mark Digitally signed by Mark Seggel Seggel Date: 9/11/2019 12:53:36PM GUID: 507572b5000036176969356148025bae

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LABELING R. Regional Information

1.14 Labeling The labeling information updated in the 3/6/2019 amendment (SD-6) is included below.

I. Package Insert

1. HIGHLIGHTS OF PRESCRIBING INFORMATION

1) Title BONSITY (teriparatide [ (b) (4) injection) for subcutaneous use Initial U.S. Approval: 2019

2) DOSAGE FORMS AND STRENGTHS (b) (4) (pen) containing 28 daily doses of 20 mcg

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Reviewer’s Comment and Item Information Provided in NDA Recommendations Drug name [201.57(a)(2)] Proprietary name and established name BONSITY (teriparatide [ (b) (4) Unacceptable. injection) The title of USP monograph, i.e. “teriparatide injection”, is the established name. “[ (b) (4) should be deleted from 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 2019 Unacceptable. The year “1987” should be listed since it was the year FDA initially approved teriparatide as NME for Parathar (discontinued in 1999). Dosage Forms and Strengths [201.57(a)(8)] Dosage Forms and Strengths Dosage form not included. Unacceptable. Strength is not provided. Dosage form “injection” and strength “620 mcg/2.48 mL (250 mcg/mL)” should be included. Whether the drug product is scored N/A N/A

Package type (b) (4) Unacceptable. The package type should be revised to “single-patient-use” 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

Conclusion: Unsatisfactory The recommended revisions are shown below:

BONSITY (teriparatide [ (b) (4) injection) for subcutaneous use Initial U.S. Approval: 2019 1987

Injection: 620 mcg/2.48 mL (250 mcg/mL) in single-patient-use pens (b) (4)

2. FULL PRESCRIBING INFORMATION

1) #3: DOSAGE FORMS AND STRENGTHS

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QUALITY ASSESSMENT

(b) (4) containing 28 daily doses of 20 mcg.

Reviewer’s Comment and Item Information Provided in NDA Recommendations Available dosage forms injection Acceptable

Strengths: in metric system Strength is not provided. Dosage Unacceptable. was provided instead. Strength “620 mcg/2.48 mL (250 mcg/mL)” should be included. The strength is expressed based on free base. Active moiety expression of strength The dosage 20 mcg is expressed Acceptable. with equivalence statement (if based on active moiety, i.e. free (b) (4) applicable) base.

A description of the identifying N/A N/A characteristics of the dosage forms, including shape, color, coating, scoring, and imprinting, when applicable. Package type (b) (4) Unacceptable. Package type should be revised to “single-patient-use” 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

Conclusion: Unsatisfactory The recommended revisions are shown below: Injection: 620 mcg/2.48 mL (250 mcg/mL)

(b) (4) Single-patient-use pen containing 28 daily doses of 20 mcg.

2) #11: DESCRIPTION

BONSITY (teriparatide [ (b) (4) injection) (b) (4) recombinant human parathyroid hormone (b) (4) 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.

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QUALITY ASSESSMENT

Teriparatide has a molecular weight of 4117.8 daltons and its amino acid sequence is shown below:

Teriparatide ( (b) (4) 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 (b) (4) delivery device (pen) for subcutaneous injection. Each prefilled delivery device is filled (b) (4) to deliver 2.48 mL. Each mL contains 250 mcg teriparatide ( (b) (4) 0.41 mg glacial acetic acid, 0.10 mg sodium acetate, 45.4 mg mannitol, 3 mg metacresol, and water for injection.

Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days.

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Reviewer’s Comment and Item Information Provided in NDA Recommendations Proprietary name and BONSITY (teriparatide [ (b) (4) Unacceptable. established name injection) “ (b) (4) should be deleted from the established name. Dosage form and route of injection, subcutaneous Acceptable administration Active moiety expression of Strength (250 mcg/mL) is expressed based on Acceptable. strength with equivalence active moiety (free base). (b) (4) statement (if applicable)

Inactive ingredient information Each mL contains 0.41 mg glacial acetic acid, Unacceptable. [quantitative, if injectables 0.10 mg sodium acetate, 45.4 mg mannitol, 3 (b) (4) 21CFR201.100(b)(5)(iii), listed mg metacresol, and water for injection. by USP/NF names (if any)]

Statement of being sterile (if “sterile” is included Acceptable applicable) Pharmacological/ therapeutic (b) (4) Unacceptable. class For clarity, change it to “human parathyroid hormone analog Chemical name, structural Chemical name is not provided, but amino acid Acceptable. formula, molecular weight sequence is provided. For a 34-amino acid peptide, the Molecular weight: 4117.8 daltons use of three-letter code to express Structural formula is provided as the primary the primary structure, in lieu of sequence using three-letter code for each amino the chemical name or structural acid. formula, is acceptable. If radioactive, statement of N/A N/A important nuclear characteristics. Other important chemical or pH information is not provided. Unacceptable. physical properties (such as pKa The formulation pH (4.0) should or pH) be included. It is also recommended to include molecular formula C181H291N55O51S2 Package type Not provided Unacceptable. Add “single-patient-use”

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QUALITY ASSESSMENT

Conclusion: Unsatisfactory

The recommended revisions are shown below: BONSITY (teriparatide [ (b) (4) injection) contains recombinant teriparatide, which is a human parathyroid hormone analog (b) (4) and is also called rhPTH (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 (b) (4) (b) (b) (4) molecular weight (4)is 4117.8 daltons. Its amino acid sequence is shown below:

Teriparatide ( (b) (4) 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 (b) (4) delivery device (pen) for subcutaneous injection. Each (b) (4) pen is filled (b) (4) to deliver 2.48 mL. Each mL contains 250 mcg teriparatide ( (b) (4) as a free base (b) (4) 0.41 mg glacial acetic acid, 0.10 mg sodium acetate, 45.4 mg mannitol, 3 mg metacresol, and water for injection. (b) (4)

Each cartridge, pre-assembled into a delivery device, delivers 20 mcg of teriparatide per dose each day for up to 28 days.

3) #16: HOW SUPPLIED/STORAGE AND HANDLING 16.1 How Supplied (b) (4) in the following package size:  (b) (4) NDC #####-###-##. 16.2 Storage and Handling

 The BONSITY delivery device should be stored under refrigeration at 2°C to 8°C (36°F to 46°F) at all times.

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 Recap the delivery device when not in use to protect the cartridge from physical damage and light.

 During the use period, time out of the refrigerator should be minimized; the dose may be delivered immediately following removal from the refrigerator.

 Do not freeze. Do not use BONSITY if it has been frozen.

Reviewer’s Comment and Item Information Provided in NDA Recommendations Strength of dosage form Strength is not provided. Unacceptable. Strength “620 mcg/2.48 mL (250 mcg/mL)” should be included. Available units (e.g., bottles (b) (4) Unacceptable. of 100 tablets) See above for strength information. Identification of dosage Actual NDC number not provided Unacceptable. forms, e.g., shape, color, Actual NDC number should be coating, scoring, imprinting, provided NDC number Special handling (e.g., protect Do not freeze. Recap the delivery device Acceptable from light) when not in use. Storage conditions stored under refrigeration at 2°C to 8°C (36°F Acceptable to 46°F) Package Type Not provided Unacceptable Add “single-patient-use pens” as package type 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.

Conclusion: Unsatisfactory The recommended revisions are shown below: 16.1 How Supplied (b) (4) BONSITY (b) (4) is available as single-patient-use pens in the following package size: • (b) (4) mcg/2.48 mL (250 mcg/mL) NDC ##### ###-##.

4) #17: PATIENT COUNSELING INFORMATION

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QUALITY ASSESSMENT

Reviewer’s Comment and Item Information Provided in NDA Recommendations Manufacturer/distributor Marketed by: Pfenex, Inc. Acceptable name [21 CFR 201.1(h)(5)] San Diego, CA 92121, USA

Conclusion: Satisfactory

II. Labels

1. IMMEDIATE CONTAINER (b) (4)

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Reviewer’s Comment and Item Information Provided in NDA Recommendations Proprietary name, established BONSITY Unacceptable. name [font size and prominence, teriparatide [ (b) (4) injection “[ (b) (4) should be deleted 21 CFR 201.10(g)(2)] from the established name. The font size of established name is greater than 50% of the proprietary name. Route of administration, if it is subcutaneous Acceptable not for oral use Dosage strength 620 mcg/2.48 mL Unacceptable. “(250 mcg/mL)” should be included for strength. The strength should be placed directly underneath the established name. Net content [21 CFR 201.51(a)] 620 mcg/2.48 mL Acceptable Name of all inactive ingredients Not provided. Acceptable. per 201.10(a) [except for oral Due to limited space, it is acceptable drug per 201.100(b)(5) or limited that inactive ingredients are not listed space per 201.10(i)(2)] per 201.10(i)(2). “Rx only” displayed prominently Not provided. Unacceptable. on the main panel Need to add “Rx only” NDC number [21 CFR 201.2 or Not provided. Per 21 CFR 201.2, NDC number is 21 CFR 207.35(b)(3)(i)] requested, but not required on all drug labeling, including the label of any prescription drug container furnished to a consumer. Therefore, NDC number will be requested if space is permitted. Lot number (21 CFR 201.18) and The location of Lot number and expiration Acceptable expiration date (21 CFR 201.17) date are allocated. Storage conditions Refrigerate – do not freeze Acceptable. Even though no numerical temperature is provided, it is considered acceptable due to space limitation. Numerical temperature range is provided in the carton label. Bar code (21CFR 201.25) Not provided. Unacceptable. Need to add Bar Code Name of manufacturer/distributor Marketed by: Pfenex, Inc. Acceptable San Diego, CA 92121, USA Others, if space is available Throw away 28 days after first use. Acceptable Package type Not provided. Unacceptable. The “statement “20 mcg per dose” is a repeated statement. “single-patient use” should be included for package type. It is recommended to replace “ (b) (4)

” with “Each single-patient-use pen will deliver 28 subcutaneous doses”.

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.” Name of all inactive ingredients. Each mL contains 0.41 mg glacial acetic Unacceptable. Quantitative ingredient acid, 0.10 mg sodium acetate, 45.4 mg (b) (4) information is required for mannitol, 3 mg metacresol, and water for injectables. injection

“Rx only” displayed prominently “Rx only” is provided. Unacceptable. on the main panel The statement is not sufficiently prominent. Statement of being sterile (if “Sterile” is provided Acceptable applicable) NDC number [21 CFR NDC number (0000-0000-00) is provided, Unacceptable. 207.35(b)(3)(i)] but not the actual number. Actual NDC number should be provided.

Lot number (21 CFR 201.18) and Not provided or allocated. Unacceptable expiration date (21 CFR 201.17) Storage conditions Keep in refrigerator at 2° to 8° (36° to Acceptable 46°F). Do not freeze. Bar code (21CFR 201.25) Bar Code is allocated. Acceptable

“See package insert for dosage Not provided. Unacceptable information” “Keep out of reach of children” Not provided. Acceptable (Required for OTC in CFR. Optional for Rx drugs) Name of manufacturer/distributor Marketed by: Pfenex, Inc. Acceptable San Diego, CA 92121, USA Others, if space is available Not a child-resistant container. Acceptable

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Package type Not provided. Unacceptable. “single-patient-use” should be included for package type. It is recommended to replace “ (b) (4)

” with “Each single-patient-use pen will deliver 28 subcutaneous doses”.

III. LIST OF DEFICIENCIES: A. Regarding PI

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:”

6. Include the package type “single-patient-use”. Delete “ (b) (4) and “ (b) (4)

7. Replace “ (b) (4) with “as a free base (b) (4) 8. (b) (4)

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(b) (4)

B. Regarding of the Container/Carton Labels: 10. Address the following for both container and carton labels: a 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 b Place the strength “620 mcg/2.48 mL (250 mcg/mL)” directly underneath the established name c The “Rx only” statement should be displayed prominently d Replace “ (b) (4) ” with “Each single-patient-use pen will deliver 28 subcutaneous doses” 11. Address the following to the container label: a Add a statement “Rx only” b Add Bar code c Add NDC number if space is permitted 12. Address the following to the carton label: (b) (4) a

b Add “See package insert for dosage information”. c Indicate the locations of Lot number and expiration date. d Provide the actual NDC number e Delete the statement “ (b) (4) ”

Reference ID: 44902224503479

QUALITY ASSESSMENT

IV. OVERALL ASSESSMENT AND RECOMMENDATION: Issues on established name, strength, dosage form, package type, lack of actual NDC number, Lot number, expiration date, and incomplete inactive ingredient list are identified for the container label, carton labeling, and package insert .

Recommendation: From the ONDP perspective, this application is not ready for approval in its present form per 21 CFR 314.125(b)(6) until the deficiencies delineated above are satisfactorily resolved.

Primary Labeling Reviewer Name and Date:

Jane Chang, Ph.D. Senior reviewer DNDP II/ONDP April 26, 2019

Secondary Reviewer Name and Date (and Secondary Summary, as needed):

I agree with Dr. Chang’s assessment and concur with her recommendation that this application is not ready for approval as of this review from the ONDP perspective.

Moo-Jhong Rhee, Ph.D. Chief, Branch V DNDP II/ONDP

Reference ID: 44902224503479 Jane Digitally signed by Jane Chang Chang Date: 4/29/2019 08:20:32AM GUID: 5034f819000053b21e2574590781f330

Moo Jhong Digitally signed by Moo Jhong Rhee Rhee Date: 4/29/2019 08:33:52AM GUID: 502d0913000029f9798ca689a802fa55

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Reference ID: 44902224503479 CHAPTER VII: MICROBIOLOGY

Product Information NDA Number 211939 Assessment Cycle Number 01 Drug Product Name/ Strength PF708 (teriparatide [ (b) (4) injection), 20 mcg/dose Route of Administration Subcutaneous Applicant Name Pfenex, Inc. Therapeutic Classification/ Type 5- New Formulation or New Manufacturer OND Division / ODEIII-DBRUP (b) (4) Manufacturing Site

Method of Sterilization The drug product is sterilized (b) (4)

Assessment Recommendation: Adequate

Assessment Summary:

List Submissions being assessed:

Document(s) Assessed Date Received

0001 7 December 2018 (original) 0011 03 April 2019 (Amendment) 0016 03 May 2019 (IR Response) 0019 22 May 2019 (IR Response) 0025 24 June 2019 (IR Response)

Highlight Key Issues from Last Cycle and Their Resolution: N/A

Remarks: The drug product is a 34-amino acid recombinant analog of human parathyroid hormone (rhPTH[1-34]) for treatment of osteoporosis and increase in bone mass. The preserved combination drug product is administered by a manually operated, fixed-dose pen injector. Some of the tables and diagrams used in this review have been adapted from the application.

Concise Description of Outstanding Issues: None

(b) (4) (b) (4) Supporting Documents: DMF (b) (4) (Type III) from and the associated microbiology review (b) (4) doc (adequate, dated 10 April 2019) are referenced for information on the (b) (4) process. DMF (b) (4) (Type V) from (b) (4) and the associated microbiology review (b) (4) .doc (adequate,

OPQ-XOPQ-TEM-0001v06 Page 1 Effective Date: February 1, 2019

Reference ID: 44902224503479 dated 08 May 2019) are referenced for information on the (b) (4) process. LOAs for both DMFs are provided.

S. DRUG SUBSTANCE

The drug substance, teriparatide, is manufactured by (b) (4) . The microbiological limits for the drug substance are (b) EU/mg for endotoxins, (4) (b) (4) CFU/10 mL for TAMC and TYMC; (b) (4) , it will not be reviewed further.

P.1 DESCRIPTION OF THE COMPOSITION OF THE DRUG PRODUCT (Section 3.2.P.7, Container Closure System-cartridge)

 Description of drug product – The drug product is a sterile, colorless, aqueous, isotonic solution for subcutaneous injection. The drug product solution is delivered from a manually operated, fixed-dose pen injector that delivers 20 mcg teriparatide per 80-µL dose subcutaneous injection once daily for 28 days. The finished drug product (pen injector) is disposed 28 days after first use and is not reused or reloaded.

 Drug product composition –

(b) (4)

 Description of container closure system – The primary container closure system of the subject drug product that is in contact with the drug solution consists of a 3 mL glass cartridge, seal with crimp cap, and plunger. The secondary container closure system consists of a protective cover (white cap), clear cartridge holder, and injector body with a black injection button.

Primary container Description Manufacturer/ DMF Component Glass cartridge (b) (4) 3 mL

Reference ID: 44902224503479 Primary container Description Manufacturer/ DMF Component (b) (4)

(b) (4) seal (b) (4)

Plunger

(b) (4)

Assessment: Adequate The applicant provided an adequate description of the drug product composition and the container closure system designed to maintain product sterility.

P.2 PHARMACEUTICAL DEVELOPMENT

P.2.5 MICROBIOLOGICAL ATTRIBUTES Container/Closure and Package Integrity (Section 3.2.P.2, Microbiological Attributes, pp. 2-3)

Reference ID: 44902224503479 Microbial Ingress Test The primary container closure system (cartridge) was used for the microbial ingress testing. Brevundimonas diminuta, with a concentration of 2 x 106 CFU/mL was used as the challenge organism. A total of 80 cartridges were filled with sterile growth medium and were subjected to two pre-conditioning temperatures (40 samples at 2-8°C for 24 hours; 40 samples at 55-60°C for 24 hours). The container closure systems were immersed immediately after preconditioning in the microbial bath for 30 minutes. After immersion the test samples were disinfected and incubated for 14 days at 30- 35°C. Positive controls and growth promotion test (after incubation) were performed. No growth was observed in the exposed cartridges, while growth was observed in the positive controls and growth promotion samples. The applicant concluded that the microbial ingress test demonstrated that the primary container closure system could maintain acceptable integrity against a microbial challenge.

The applicant did not use pressure/vacuum for the test, the positive controls were not described, and it is unclear if the containers were exposed to the routine (b) (4) process prior to the container closure integrity test (CCIT). Additional information will be requested.

(b) (4)

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Reference ID: 44902224503479 (b) (4)

Assessment: Adequate The applicant’s verification of container closure integrity is consistent with regulatory expectations for a sterile pharmaceutical product.

Antimicrobial Effectiveness Testing (Section 3.2.P.2, Microbiological Attributes, pp. 1-2, Section 1.11.1, Quality Information Amendment, dated 04/03/19)

 The drug product is formulated with (b) (4)  Dug product specification: (b) (4) Preservative Efficacy Study Antimicrobial effectiveness testing (AET) was performed according to USP <51> on three exhibit batches (ANS299, ANS300, and ANS301) containing (b) (4) preservative concentrations of (b) (4) mg/mL (103%), (b) (4) mg/mL (80%), and (b) (4) mg/mL (53%), respectively. The applicant states that results from the study show that the USP <51>, category 1 requirements for antimicrobial effectiveness were met at all three (b) (4) levels. The results are summarized as follows:

Initial Lot ANS299 Lot ANS300 Lot ANS301 conc. in LR Result LR Result LR Result Organism product Day Day Day Day Day Day Day Day Day (CFU/mL) 7 14 28 7 14 28 7 14 28 P. aeruginosa 1.9 x 105 > 4.0 > 4.0 NI > 4.0 > 4.0 NI > 4.0 > 4.0 NI E. coli 3.4 x 105 > 4.0 > 4.0 NI > 4.0 > 4.0 NI > 4.0 > 4.0 NI S. aureus 5.5 x 105 > 4.0 > 4.0 NI > 4.0 > 4.0 NI > 4.0 > 4.0 NI C. albicans 2.1 x 105 NI NI NI NI NI NI NI NI NI A. brasiliensis 1.8 x 105 NI NI NI NI NI NI NI NI NI LR= Log reduction, NI= No increase

AET Stability Study The AET was performed on Lot 1614-003A002 stored at 2-8 ºC at the 24 months stability time point. The test was performed per USP <51> on day 7, 14, and 28. The study shows that the USP <51>, category 1 requirements for antimicrobial effectiveness test were met for the drug product at the end of shelf-life. The results are summarized as follows:

Reference ID: 44902224503479 Lot ANS299 Initial conc. in product Organism LR Result (CFU/mL) Day 7 Day 14 Day 28 P. aeruginosa 2.9 x 105 > 4.0 > 4.0 NI E. coli 2.0 x 105 > 4.0 > 4.0 NI 5 S. aureus 6.0 x 10 > 4.0 > 4.0 NI 5 NI NI NI C. albicans 2.2 x 10 A. brasiliensis 5.5 x 105 NI NI NI LR= Log reduction, NI= No increase

Assessment: Adequate The applicant has met regulatory expectations for demonstrating the antimicrobial effectiveness requirement for a multiple dose drug product.

P.3 MANUFACTURE

P.3.1 MANUFACTURERS (b) (4)

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Reference ID: 44902224503479 Maritere Digitally signed by Maritere Carattini Carattini Date: 7/02/2019 12:06:50PM GUID: 5a99a9800059de20999699de06332d80

John Digitally signed by John Metcalfe Metcalfe Date: 7/02/2019 12:08:03PM GUID: 503451f000004f68b7145543c615dbba Comments: I concur with the primary reviewer's assessment.

Reference ID: 44902224503479 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 09/11/2019 01:49:23 PM

Reference ID: 44902224503479