HQ Specialty Pharma CorporationCefazolin for Injection USP, 2 g/vial

NDA 211413 COMPLETE RESPONSE

HQ Specialty Pharma Corporation Attention: Jeanne Squeglia

Vice President, Technical

120 Route 17 North

Paramus, NJ 07652

Dear Ms. Squeglia:

Please refer to your New Drug Application (NDA) dated December 21, 2017, received December 21, 2017, and your amendments, submitted pursuant to section 505(b)(2) of the Federal Food, Drug, and Cosmetic Act for Cefazolin for Injection USP, 2 g/vial.

We have completed our review of this application, as amended, and have determined that we cannot approve this application in its present form. We have described our reasons for this action below and, where possible, our recommendations to address these issues.

CLINICAL

1. You have not provided adequate information to support the safety of 2-gram cefazolin ww )

NONCLINICAL and PRODUCT QUALITY

Leachables

2. You have not provided adequate support for the assigned structures of the leachables. The original program assigned CAS numbers to both leachables that could not be found in the literature or databases. In your response dated September 14, 2018, you confirmed that the program used in the leachables study erroneously provided the CAS numbers, and that both leachables do not have CAS numbers. Also, no information was provided regarding the validity of the assigned structures of the leachables from this program. Since neither of these leachables are identified in the literature, it is not clear how the structures of these leachables were assigned.

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In the absence of valid, reliable structures for the two leachables that exceed the safety qualification threshold of 5 mcg/day, the results obtained using the computational QSAR methodology and read across toxicology assessments with structurally similar compounds and hydrolysis products are of questionable utility.

Information needed to resolve the deficiency

e Additional characterization data should be submitted to support the structures of these leachables. Refer to USP <1663> and USP <1664>.

¢ Once you have provided additional characterization data to support the proposed structures of these two leachables or have included revised structures with greater structural certainty, conduct additional QSAR evaluation(s) and revised comprehensive toxicological assessment(s) to justify the safety of these identified compounds as needed.

3. The acceptability of the proposed stopper cannot be determined until the identity of the leachables has been established, and the safety profile of the leachables is considered acceptable from a nonclinical perspective.

Impurities

4. The drug product specifications provided in the September 14, 2018 amendment, with the

unspecified impurities (RRT ©) above the identification and qualification thresholds, are inadequate. The referenced ANDA Guidance is not applicable to this NDA.

Information needed to resolve the deficiency ¢ Qualification data should be submitted for all impurities above the qualification threshold. e Additional nonclinical studies may be needed to qualify any impurities that exceed the safety qualification threshold described in ICH Guidance Q3B(R2) ‘Impurities in New Drug Products’.!

5. No characterization data or descriptions of laboratory studies demonstrating efforts to identify the structures were submitted for the specified unidentified impurities in the drug product specifications. The only information provided for these impurities was the relative retention time (RRT). This is not adequate, as the impurities are above the identification threshold.

Information needed to resolve the deficiency Submit the characterization data for the unidentified specified impurities above the identification threshold in the drug product specifications.

' https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatorylnformation/Guidances/ UCM 073389.pdf

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6. The analytical procedures were updated to describe the measurement of the three specified unidentified impurities, but the method was not validated for the measurement of these unspecified impurities.

Information needed to resolve the deficiency The analytical methods should be validated for the measurement of the specified impurities in the drug product specifications.

PRESCRIBING INFORMATION

We reserve comment on the proposed labeling until the application is otherwise adequate. We encourage you to review the labeling review resources on the PLR Requirements for Prescribing Information and Pregnancy and Lactation Labeling Final Rule websites, including regulations and related guidance documents and the Selected Requirements for Prescribing Information (SRPI) — a checklist of important format items from labeling regulations and guidances.

If you revise labeling, use the SRPI checklist to ensure that the prescribing information conforms with format items in regulations and guidances. Your response must include updated content of labeling [21 CFR 314.50(1)(1)(i)] in structured product labeling (SPL) format as described at http://www.fda.gov/ForIndustry/DataS tandards/StructuredProductLabeling/default.htm

CARTON AND CONTAINER LABELING Submit draft carton and container labeling revised as follows: Container Label

To minimize confusion and reduce the risk for deteriorated drug medication errors, identify the format you intend to use. We recommend using a format like either:

DDMMMYYYY (e.g., 31JAN2013) MMMYYYY (e.g., JAN2013) YYYY-MMM-DD (e.g., 2013- JAN-31) YYYY-MM-DD (e.g., 2013-01-31)

Carton Label

Include the lot number statement and expiration date. When determining this placement, please ensure that there are no other numbers located in close proximity to the lot number/expiration date that can be mistaken as the lot number/expiration date. Additionally, to minimize confusion and reduce the risk for deteriorated drug medication errors, identify the format you intend to use. For the format of the expiration date, we recommend using a format like either:

DDMMMYYYY (e.g., 31JAN2013) MMMYYYY (e.g., JAN2013) YYYY-MMM-DD (e.g., 2013- JAN-31) YYYY-MM-DD (e.g., 2013-01-31)

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Carton and Container Labels

1. We recommend that the barcode on the container label be oriented in the vertical position to improve scannability, as barcodes placed in a horizontal position may not scan due to the curvature of the container. Additionally, we request that you add the product barcode to the carton labeling.

2. To provide differentiation between the carton and vials within the carton, revise the NDC package code numbers (last 2 digits) so that the container (vial) label and carton labeling NDC numbers are different. Additionally, if you opt to change the carton labeling NDC, update the NDC number in Section 16, How Supplied/Storage and Handling of the Full Prescribing Information as appropriate.

3. Add the Centigrade symbol (C) following 20° and 2° and Fahrenheit symbol (F) following 68° and 36° within the storage information to provide clarity. For example, “Before reconstitution store at 20°C to 25°C (68°F to 77°F) [see USP Controlled Room Temperature]. After reconstitution: Stable for @hours at room temperature o1 | days if refrigerated 2°C to 8°C (36°F to 46°F).”

4. To minimize the potential for misinterpretation of the equivalency statement, we recommend replacing all instances of the abbreviation “g” with the intended meaning “grams.” For example, “...equivalent to 2 grams of cefazolin.”

5. Relocate the statement “PROTECT FROM LIGHT” such that it follows the “Before reconstitution” storage statement. For example, “Before reconstitution store at....Room Temperature]. PROTECT FROM LIGHT. After reconstitution: Stable...”

6. Add the appropriate package type (i.e., Single-Dose Vial) to the principal display panel (PDP).

7. Revise the statement © on the PDP to read “Single-Dose Vial — Discard Unused Portion.” Additionally, we recommend that you bold the font of the statement “Discard unused portion” to increase the prominence of this important information. For example, “Single-Dose Vial — Discard Unused Portion.”

ADDITIONAL COMMENTS

In the Pre-NDA meeting minutes dated August 26, 2016, the Division noted that your presentation of cefazolin powder in a 2-gram vial would not trigger the Pediatric Research and Equity Act (PREA). | oa) OO Tn your complete response, please address your plans for pediatric assessment.

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SAFETY UPDATE

When you respond to the above deficiencies, include a safety update as described at

21 CFR 314.50(d)(5)(vi)(b). The safety update should include data from all nonclinical and clinical studies/trials of the drug under consideration regardless of indication, dosage form, or dose level.

1. Describe in detail any significant changes or findings in the safety profile.

2. When assembling the sections describing discontinuations due to adverse events, serious adverse events, and common adverse events, incorporate new safety data as follows:

e Present new safety data from the studies/clinical trials for the proposed indication using the same format as in the original submission.

¢ Present tabulations of the new safety data combined with the original application data.

e Include tables that compare frequencies of adverse events in the original application with the retabulated frequencies described in the bullet above.

e For indications other than the proposed indication, provide separate tables for the frequencies of adverse events occurring in clinical trials.

3. Present a retabulation of the reasons for premature trial discontinuation by incorporating the drop-outs from the newly completed trials. Describe any new trends or patterns identified.

4. Provide case report forms and narrative summaries for each patient who died during a clinical trial or who did not complete a trial because of an adverse event. In addition, provide narrative summaries for serious adverse events.

5. Describe any information that suggests a substantial change in the incidence of common, but less serious, adverse events between the new data and the original application data.

6. Provide updated exposure information for the clinical studies/trials (e.g., number of subjects, person time).

7. Provide a summary of worldwide experience on the safety of this drug. Include an updated estimate of use for drug marketed in other countries.

8. Provide English translations of current approved foreign labeling not previously submitted. OTHER

Within one year after the date of this letter, you are required to resubmit or take other actions available under 21 CFR 314.110. If you do not take one of these actions, we may consider your

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lack of response a request to withdraw the application under 21 CFR 314.65. You may also request an extension of time in which to resubmit the application.

A resubmission must fully address all the deficiencies listed in this letter and should be clearly marked with "RESUBMISSION" in large font, bolded type at the beginning of the cover letter of the submission. The cover letter should clearly state that you consider this resubmission a complete response to the deficiencies outlined in this letter. A partial response to this letter will not be processed as a resubmission and will not start a new review cycle.

You may request a meeting or teleconference with us to discuss what steps you need to take before the application may be approved. If you wish to have such a meeting, submit your meeting request as described in the draft FDA Guidance for Industry, “Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products,” December 2017 at https://www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM59054 7.

The drug product may not be legally marketed until you have been notified in writing that this application is approved.

If you have any questions, call Jacquelyn Rosenberger, PharmD, Regulatory Project Manager, at (301) 796-9179.

Sincerely,

{See appended electronic signature page} Sumathi Nambiar, MD, MPH

Director

Division of Anti-Infective Products

Office of Antimicrobial Products Center for Drug Evaluation and Research

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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.

SUMATHI NAMBIAR 10/19/2018

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